Benzylaminopyridylcyclopropanecarboxylic acids, pharmaceutical compositions and uses thereof

ABSTRACT

The present invention relates to compounds of general formula I, 
                         
wherein the groups R, R 1 , R 2 , R 3 , m and n are defined herein, which have valuable pharmacological properties, including binding to the GPR40 receptor and modulating its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2. Furthermore, the invention relates to novel intermediates, useful for the synthesis of compounds of formula I.

FIELD OF THE INVENTION

The present invention relates to novel benzylaminopyridylcyclopropanecarboxylic acids, that are agonists of the G-protein coupled receptor 40 (GPR40, also known as free fatty acid receptor FFAR 1), to processes for their preparation, to pharmaceutical compositions containing these compounds and to their medical use for the prophylaxis and/or treatment of diseases which can be influenced by the modulation of the function of GPR40. Particularly, the pharmaceutical compositions of the invention are suitable for the prophylaxis and/or therapy of metabolic diseases, such as diabetes, more specifically type 2 diabetes mellitus, and conditions associated with the disease, including insulin resistance, obesity, cardiovascular disease and dyslipidemia.

BACKGROUND OF THE INVENTION

Metabolic diseases are diseases caused by an abnormal metabolic process and may either be congenital due to an inherited enzyme abnormality or acquired due to a disease of an endocrine organ or failure of a metabolically important organ such as the liver or the pancreas.

Diabetes mellitus is a disease state or process derived from multiple causative factors and is defined as a chronic hyperglycemia associated with resulting damages to organs and dysfunctions of metabolic processes. Depending on its etiology, one differentiates between several forms of diabetes, which are either due to an absolute (lacking or decreased insulin secretion) or to a relative lack of insulin. Diabetes mellitus Type I (IDDM, insulin-dependent diabetes mellitus) generally occurs in adolescents under 20 years of age. It is assumed to be of auto-immune etiology, leading to an insulitis with the subsequent destruction of the beta cells of the islets of Langerhans which are responsible for the insulin synthesis. In addition, in latent autoimmune diabetes in adults (LADA; Diabetes Care. 8: 1460-1467, 2001) beta cells are being destroyed due to autoimmune attack. The amount of insulin produced by the remaining pancreatic islet cells is too low, resulting in elevated blood glucose levels (hyperglycemia). Diabetes mellitus Type II generally occurs at an older age. It is above all associated with a resistance to insulin in the liver and the skeletal muscles, but also with a defect of the islets of Langerhans. High blood glucose levels (and also high blood lipid levels) in turn lead to an impairment of beta cell function and to an increase in beta cell apoptosis.

Persistent or inadequately controlled hyperglycemia is associated with a wide range of pathologies. Diabetes is a very disabling disease, because today's common antidiabetic drugs do not control blood sugar levels well enough to completely prevent the occurrence of high and low blood sugar levels. Out of range blood sugar levels are toxic and cause long-term complications for example retinopathy, renopathy, neuropathy and peripheral vascular disease. There is also a host of related conditions, such as obesity, hypertension, stroke, heart disease and hyperlipidemia, for which persons with diabetes are substantially at risk.

Obesity is associated with an increased risk of follow-up diseases such as cardiovascular diseases, hypertension, diabetes, hyperlipidemia and an increased mortality. Diabetes (insulin resistance) and obesity are part of the “metabolic syndrome” which is defined as the linkage between several diseases (also referred to as syndrome X, insulin-resistance syndrome, or deadly quartet). These often occur in the same patients and are major risk factors for development of diabetes type II and cardiovascular disease. It has been suggested that the control of lipid levels and glucose levels is required to treat diabetes type II, heart disease, and other occurrences of metabolic syndrome (see e.g., Diabetes 48: 1836-1841, 1999; JAMA 288: 2209-2716, 2002).

The free fatty acid receptor GPR40 (also referred to as either FFAR, FFAR1, or FFA1) is a cell-surface receptor and a member of the gene superfamily of G-protein coupled receptors, which was first identified as a so-called orphan receptor, i.e. a receptor without a known ligand, based on the predicted presence of seven putative transmembrane regions in the corresponding protein (Sawzdargo et al. (1997) Biochem. Biophys. Res. Commun. 239: 543-547). GPR40 is found to be highly expressed in several particular cell types: the pancreatic β cells and insulin-secreting cell lines, as well as in enteroendocrine cells, taste cells, and is reported to be expressed in immune cells, splenocytes, and in the human and monkey brain. Meanwhile, fatty acids of varying chain lengths are thought to represent the endogenous ligands for GPR40, activation of which is linked primarily to the modulation of the Gq family of intra-cellular signaling G proteins and concomitant induction of elevated calcium levels, although activation of Gs- and Gi-proteins to modulate intracellular levels of cAMP have also been reported. GPR40 is activated especially by long-chain FFA, particularly oleate, as well as the PPAR-gamma agonist rosiglitazone.

It has been recognized that the fatty acids that serve as activators for GPR40 augment the elevated plasma glucose-induced secretion of insulin through GPR40 receptors that are expressed in the insulin secreting cells (Itoh et al. (2003) Nature 422: 173-176; Briscoe et al. (2003) J. Biol. Chem. 278: 11303-11311; Kotarsky et al. (2003) Biochem. Biophys. Res. Commun. 301: 406-410). Despite initial controversy, the use of GPR40 agonist appears to be the appropriate for increasing insulin release for the treatment of diabetes (see e.g. Diabetes 2008, 57, 2211; J. Med. Chem. 2007, 50, 2807). Typically, long term diabetes therapy leads to the gradual diminution of islet activity, so that after extended periods of treatment Type 2 diabetic patients need treatment with daily insulin injections instead. GPR40 agonists may have the potential to restore or preserve islet function, therefore, GPR40 agonists may be beneficial also in that that they may delay or prevent the diminution and loss of islet function in a Type 2 diabetic patient.

It is well established that the incretins GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide; also known as gastric inhibitory peptide) stimulate insulin secretion and are rapidly inactivated in vivo by DPP-4. These peptidyl hormones are secreted by endocrine cells that are located in the epithelium of the small intestine. When these endocrine cells sense an increase in the concentration of glucose in the lumen of the digestive tract, they act as the trigger for incretin release. Incretins are carried through the circulation to beta cells in the pancreas and cause the beta cells to secrete more insulin in anticipation of an increase of blood glucose resulting from the digesting meal. Further studies indicating that the GPR40 modulatory role on the release of incretins from the enteroendocrine cells, including CCK, GLP-1, GIP, PYY, and possibly others, suggest that GPR40 modulators may contribute to enhanced insulin release from the pancreatic beta cells also indirectly by e.g. a synergistic effect of GLP-1 and possibly GIP on the insulin release, and the other release incretins may also contribute to an overall beneficial contribution of GPR40 modulation on metabolic diseases. The indirect contributions of GPR40 modulation on insulin release through the elevation of plasma levels of incretins may be further augmented by the coadministration of inhibitors of the enzymes responsible for the incretin degradation, such as inhibitors of DPP-4.

Insulin imbalances lead to conditions such as type II diabetes mellitus, a serious metabolic disease. The modulation of the function of GPR40 in modulating insulin secretion indicates the therapeutic agents capable of modulating GPR40 function could be useful for the treatment of disorders such as diabetes and conditions associated with the disease, including insulin resistance, obesity, cardiovascular disease and dyslipidemia.

OBJECT OF THE PRESENT INVENTION

The object of the present invention is to provide new compounds, hereinafter described as compounds of formula I, in particular new benzylaminopyridylcyclopropanecarboxylic acids, which are active with regard to the G-protein-coupled receptor GPR40, notably are agonists of the G-protein-coupled receptor GPR40.

A further object of the present invention is to provide new compounds, in particular new benzylaminopyridylcyclopropanecarboxylic acids, which have an activating effect on the G-protein-coupled receptor GPR40 in vitro and/or in vivo and possess suitable pharmacological and pharmacokinetic properties to use them as medicaments.

A further object of the present invention is to provide effective GPR40 agonists, in particular for the treatment of metabolic disorders, for example diabetes, dyslipidemia and/or obesity.

A further object of the present invention is to provide methods for treating a disease or condition mediated by the activation the G-protein-coupled receptor GPR40 in a patient.

A further object of the present invention is to provide a pharmaceutical composition comprising at least one compound according to the invention.

A further object of the present invention is to provide a combination of at least one compound according to the invention with one or more additional therapeutic agents.

Further objects of the present invention become apparent to the one skilled in the art by the description hereinbefore and in the following and by the examples.

GPR40 modulators are known in the art, for example, the compounds disclosed in WO 2004041266 (EP 1559422), WO 2007033002, WO 2009157418, and WO 2013178575. The benzylaminopyridylcyclopropanecarboxylic acids of the present invention may provide several advantages, such as enhanced potency, high metabolic and/or chemical stability, high selectivity and tolerability, enhanced solubility, and the possibility to form stable salts.

SUMMARY OF THE INVENTION

In a first aspect, the invention relates to a compound of formula

wherein

-   -   R is selected from the group R-G1 consisting of         -   H, F, Cl, Br, I, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,             C₃₋₆-cycloalkyl, NC—, HNR^(N)—C(═O)—,             C₁₋₄-alkyl-NR^(N)—C(═O)—, C₃₋₆-cycloalkyl-NR^(N)—C(═O)—,             heterocyclyl-NR^(N)—C(═O)—, heteroaryl-NR^(N)—C(═O)—, HOOC—,             C₁₋₄-alkyl-O—C(═O)—, O₂N—, HRN^(N)—, C₁₋₄-alkyl-RN^(N)—,             C₁₋₄-alkyl-C(═O)NR^(N)—, C₃₋₆-cycloalkyl-C(═O)NR^(N)—,             heterocyclyl-C(═O)NR^(N)—, heteroaryl-C(═O)NR^(N)—,             C₁₋₄-alkyl-S(═O)₂NR^(N)—, C₃₋₆-cycloalkyl-S(═O)₂NR^(N)—,             heterocyclyl-S(═O)₂NR^(N)—, heteroaryl-S(═O)₂NR^(N)—, HO—,             C₁₋₆-alkyl-O—, HOOC—C₁₋₃-alkyl-O—,             C₃₋₆-cycloalkyl-C₁₋₃-alkyl-O—, heterocyclyl-C₁₋₃-alkyl-O—,             phenyl-C₁₋₃-alkyl-O—, C₃₋₆-cycloalkyl-O—, heterocyclyl-O—,             heteroaryl-O—, C₁₋₄-alkyl-S—, C₃₋₆-cycloalkyl-S—,             heterocyclyl-S—, C₁₋₄-alkyl-S(═O)—, C₃₋₆-cycloalkyl-S(═O)—,             heterocyclyl-S(═O)—, C₁₋₄-alkyl-S(═O)₂—,             C₃₋₆-cycloalkyl-S(═O)₂—, heterocyclyl-S(═O)₂—,             phenyl-S(═O)₂—, heteroaryl-S(═O)₂—, HNR^(N)—S(═O)₂—,             C₁₋₄-alkyl-NR^(N)—S(═O)₂—, heterocyclyl, phenyl, and             heteroaryl,         -   wherein each alkyl, cycloalkyl, and heterocyclyl group or             sub-group within the groups forming R is optionally             substituted with 1 or more F atoms and optionally             substituted with 1 to 3 groups independently selected from             Cl, C₁₋₃-alkyl, NC—, (R^(N))₂N—, HO—, C₁₋₃-alkyl-O—, and             C₁₋₃-alkyl-S(═O)₂—; and         -   wherein each phenyl and heteroaryl group or sub-group within             the groups forming R is optionally substituted with 1 to 5             substituents independently selected from F, Cl, C₁₋₃-alkyl,             HF₂C—, F₃C—, NC—, (R^(N))₂N—, HO—, C₁₋₃-alkyl-O—, F₃C—O—,             and C₁₋₃-alkyl-S(═O)₂—;         -   wherein each heterocyclyl group or sub-group within the             groups forming R is selected from             -   a cyclobutyl group wherein 1 CH₂ group is replaced by                 —NR^(N)— or —O—;             -   a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is replaced                 by —C(═O)—, —NR^(N)—, —O—, —S— or —S(═O)₂— and/or 1 CH                 group is replaced by N;             -   a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is replaced                 by —NR^(N)— or —O—, a second CH₂ group is replaced by                 —NR^(N)—, —C(═O)— or —S(═O)₂— and/or 1 CH group is                 replaced by N; and             -   a C₅₋₆-cycloalkyl group wherein 2 CH₂ groups are                 replaced by —NR^(N)— or 1 CH₂ group by —NR^(N)— and the                 other by —O— and a third CH₂ group is replaced by                 —C(═O)— or —S(═O)₂— and/or 1 CH group is replaced by N;         -   wherein each heteroaryl group or sub-group within the groups             forming R is selected from             -   tetrazolyl and a 5- or 6-membered heteroaromatic ring                 which contains 1, 2, or 3 heteroatoms independently of                 each other selected from ═N—, —NR^(N)—, —O—, and —S—,                 wherein in heteroaromatic groups containing a —HC═N—                 unit this group is optionally replaced by                 —NR^(N)—C(═O)—;         -   wherein in heteroaryl and heterocyclyl rings with one or             more NH groups, each of said NH groups is replaced by             NR^(N);     -   R¹ is selected from the group R¹-G1 consisting of H, F, Cl,         C₁₋₄-alkyl, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkyl,         C₁₋₄-alkyl-O—C₁₋₄-alkyl, NC—, HO—, C₁₋₄-alkyl-O—,         C₃₋₆-cycloalkyl-O—, C₁₋₄-alkyl-S—, C₁₋₄-alkyl-S(O)—, and         C₁₋₄-alkyl-S(O)₂—,         -   wherein any alkyl and cycloalkyl group or sub-group within             the groups forming R¹ is optionally substituted with 1 or             more F atoms, and wherein multiple R¹ may be identical or             different if m is 2, 3 or 4;     -   m is an integer selected from 1, 2, 3, and 4;     -   R² is selected from the group R²-G1 consisting of H, F, Cl,         C₁₋₄-alkyl, NC—, and C₁₋₄-alkyloxy,         -   wherein any alkyl group or sub-group within the groups             forming R² is optionally substituted with 1 or more F atoms,             and wherein multiple R² may be identical or different if n             is 2 or 3;     -   R³ is selected from the group R³-G1 consisting of H, F, Cl,         C₁₋₄-alkyl, NC—, and C₁₋₄-alkyl-O—,         -   wherein each alkyl group or sub-group within the groups             forming R³ is optionally substituted with 1 or more F atoms;     -   n is an integer selected from 1, 2, and 3;     -   R^(N) is independently of each other selected from the group         R^(N)-G1 consisting of H, C₁₋₄-alkyl, HO—C₁₋₄-alkyl-(H₂C)—,         C₁₋₃-alkyl-O—C₁₋₄-alkyl-, C₁₋₄-alkyl-C(═O)—,         C₁₋₄-alkyl-NH—C(═O)—, C₁₋₄-alkyl-N(C₁₋₄-alkyl)-C(═O)—,         C₁₋₄-alkyl-O—C(═O)—, and C₁₋₄-alkyl-S(═O)₂—,         -   wherein each alkyl group or sub-group within the groups             forming R^(N) is optionally substituted with 1 or more F             atoms;

wherein in any definition mentioned hereinbefore and if not specified otherwise, any alkyl group or sub-group may be straight-chained or branched,

the isoforms, tautomers, stereoisomers, metabolites, prodrugs, solvates, hydrates, and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, or the combinations thereof.

The extension -Gn used within the definitions is meant to identify genus n of the respective substituent. For example, R-G1 defines genus 1 of the substituent R.

The expression “optionally substituted with 1 or more F atoms” means that none or one up to successively all H atoms bound to carbon atoms of the respective group or submoiety may be replaced by F atoms, preferably 1 to 5 H atoms or, more preferred, 1 to 3 H atoms may be replaced by F atoms.

In a further aspect this invention relates to a pharmaceutical composition, comprising one or more compounds of general formula I or one or more pharmaceutically acceptable salts thereof according to the invention, optionally together with one or more inert carriers and/or diluents.

In a further aspect this invention relates to a method for treating diseases or conditions which are mediated by activating the G-protein-coupled receptor GPR40 in a patient in need thereof characterized in that a compound of general formula I or a pharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided a method for treating a metabolic disease or disorder, such as diabetes, dyslipidemia and/or obesity, in a patient in need thereof characterized in that a therapeutically effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided the use of a compound of the general formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for a therapeutic method as described hereinbefore and hereinafter.

According to another aspect of the invention, there is provided a compound of the general formula I or a pharmaceutically acceptable salt thereof for use in a therapeutic method as described hereinbefore and hereinafter.

In a further aspect this invention relates to a method for treating a disease or condition mediated by the activation of the G-protein-coupled receptor GPR40 in a patient that includes the step of administering to the patient in need of such treatment a therapeutically effective amount of a compound of the general formula I or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more additional therapeutic agents.

In a further aspect this invention relates to the use of a compound of the general formula I or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents for the treatment of diseases or conditions which are mediated by the activation of the G-protein-coupled receptor GPR40.

In a further aspect this invention relates to a pharmaceutical composition which comprises a compound according to general formula I or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents, optionally together with one or more inert carriers and/or diluents.

Other aspects of the invention become apparent to the one skilled in the art from the specification and the experimental part as described hereinbefore and hereinafter.

DETAILED DESCRIPTION

Unless otherwise stated, the groups, residues, and substituents, particularly R, R¹, R², R³, m and n are defined as above and hereinafter. If residues, substituents, or groups occur several times in a compound, they may have the same or different meanings. Some preferred meanings of individual groups and substituents of the compounds according to the invention will be given hereinafter. Any and each of these definitions may be combined with each other.

R:

R-G1:

The group R is preferably selected from the group R-G1 as defined hereinbefore.

R-G2:

In another embodiment the group R is selected from the group R-G2 consisting of

-   -   H, F, Cl, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, NC—, HNR^(N)—C(═O)—,         C₁₋₄-alkyl-NR^(N)—C(═O)—, C₃₋₆-cycloalkyl-NR^(N)—C(═O)—,         heterocyclyl-NR^(N)—C(═O)—, HOOC—, HRN^(N)—, C₁₋₄-alkyl-RN^(N)—,         C₁₋₄-alkyl-C(═O)NR^(N)—, C₃₋₆-cycloalkyl-C(═O)NR^(N)—,         heterocyclyl-C(═O)NR^(N)—, C₁₋₄-alkyl-S(═O)₂NR^(N)—, HO—,         C₁₋₆-alkyl-O—, HOOC—(C₁₋₂-alkyl)-O—, cyclopropyl-H₂C—O—,         heterocyclyl-C₁₋₂-alkyl-O—, phenyl-C₁₋₂-alkyl-O—,         C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, heteroaryl-O—,         C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl-S(═O)₂—,         heterocyclyl-S(═O)₂—, HNR^(N)—S(═O)₂—,         C₁₋₄-alkyl-NR^(N)—S(═O)₂—, heterocyclyl, and heteroaryl,     -   wherein each alkyl, cycloalkyl, and heterocyclyl group or         sub-group within the groups forming R is optionally substituted         with 1 or more F atoms and optionally substituted with 1 to 2         groups independently selected from Cl, H₃C—, NC—, R^(N)HN—, HO—,         H₃C—O—, and H₃C—S(═O)₂—;     -   wherein each heteroaryl group or sub-group within the groups         forming R is optionally substituted with 1 to 3 substituents         independently selected from F, Cl, H₃C—, F₃C—, NC—, (R^(N))₂N—,         HO—, H₃C—O—, F₃C—O—, and H₃C—S(═O)₂—;     -   wherein each heterocyclyl group or sub-group within the groups         forming R is selected from         -   a cyclobutyl group wherein 1 CH₂ group is replaced by             —NR^(N)— or —O—;         -   a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is replaced by             —C(═O)—, —NR^(N)—, —O—, —S— or —S(═O)₂— and/or 1 CH group is             replaced by N;         -   a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is replaced by             —NR^(N)— or —O—, a second CH₂ group is replaced by —NR^(N)—,             —C(═O)— or —S(═O)₂— and/or 1 CH group is replaced by N;     -   wherein each heteroaryl group or sub-group within the groups         forming R is selected from         -   tetrazolyl, a 5-membered heteroaromatic ring which contains             1, 2 or 3 heteroatoms independently of each other selected             from ═N—, —NH—, O and S, and a 6-membered heteroaromatic             ring which contains 1 or 2 ═N— atoms, wherein a —HC═N— unit             is optionally replaced by —NH—C(═O)—;     -   and wherein in each of the above heteroaryl and heterocyclyl         group or sub-group containing one or more NH, said group(s) is         replaced by NR^(N).

R-G3:

In another embodiment the group R is selected from the group R-G3 consisting of H, F, Cl, C₁₋₄-alkyl, NC—, H₂N—C(═O)—, C₁₋₃-alkyl-NR^(N)—C(═O)—, C₁₋₃-alkyl-C(═O)NR^(N)—, C₁₋₄-alkyl-S(═O)₂NR^(N)—, HO—, C₁₋₅-alkyl-O—, HOOC—CH₂—O—, cyclopropyl-H₂C—O—, heterocyclyl-CH₂—O—, phenyl-CH₂—O—, C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, heteroaryl-O—, heterocyclyl-S(═O)₂—, heterocyclyl, and heteroaryl,

-   -   wherein each alkyl, cycloalkyl, and heterocyclyl group or         sub-group within the groups forming R is optionally substituted         with 1 or more F atoms and optionally substituted with 1 group         selected from Cl, H₃C—, NC—, R^(N)HN—, HO—, H₃C—O—, and         H₃C—S(═O)₂—;     -   wherein each heteroaryl group or sub-group within the groups         forming R is optionally substituted with 1 to 2 substituents         independently selected from F, Cl, H₃C—, F₃C—, NC—, (R^(N))₂N—,         HO—, H₃C—O—, F₃C—O—, and H₃C—S(═O)₂—;     -   wherein each heterocyclyl or sub-group within the groups forming         R is selected from a cyclobutyl group wherein 1 CH₂ group is         replaced by —NR^(N)— or —O—; a C₅₋₆-cycloalkyl group wherein 1         CH₂ group is replaced by —C(═O)—, —NR^(N)—, —O—, —S— or —S(═O)₂—         and/or 1 CH group is replaced by N;     -   wherein each heteroaryl group or sub-group within the groups         forming R is selected from tetrazolyl, a 5-membered         heteroaromatic ring which contains 1, 2 or 3 heteroatoms         independently of each other selected from ═N—, —NH—, O and S,         and a 6-membered heteroaromatic ring which contains 1 or 2 ═N—         atoms, wherein a —HC═N— unit is optionally replaced by         —NH—C(═O)—;     -   and wherein in each heteroaryl and heterocyclyl group or         sub-group mentioned under R-G3 containing one or more NH, said         group(s) is replaced by NR^(N).

R-G4:

According to another embodiment the group R is selected from the group R-G4 consisting of:

H, F, Cl, NC—, H₂NC(═O)—, H₃CHN—C(═O)—, (H₃C)₂N—C(═O)—, HO—;

C₁₋₃-alkyl optionally substituted with 1 or more F or optionally monosubstituted with HO—;

cyclopropyl optionally monosubstituted with NC—;

H₃C—O— optionally monosubstituted with C₁₋₄-alkyl, HOOC—, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, or phenyl,

-   -   wherein the C₁₋₄-alkyl group optionally attached to H₃C—O— is         optionally monosubstituted with NC—, HO— or H₃C—S(═O)₂—, and     -   wherein said oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,         tetrahydrothiopyranyl, and 1,1-dioxotetrahydrothiopyranyl groups         are optionally monosubstituted with H₃C— or HO—;

cyclopropyl-H₂C—O—, cyclopropyl-O—, tetrahydrofuranyl-O— and tetrahydropyranyl-O—; and

a heteroaryl group selected from pyrazolyl, [1,2,4]oxadiazolyl, tetrazolyl, pyridyl, pyridin-2-onyl, pyrazinyl, pyrimidinyl, pyrimidin-2-onyl, and pyrimidin-4-onyl,

-   -   wherein each of said heteroaryl groups is optionally         monosubstituted with H₃C—, and     -   wherein each H—N group in said heteroaryl groups is optionally         replaced with H₃C—N or (H₃C)₂C(OH)—H₂C—N,

and 2-methoxypyridin-4-yl.

R-G5:

In another embodiment the group R is selected from the group R-G5 consisting of

H, F, Cl, H₃C—, H₃C—H₂C—, (H₃C)₂CH—,

F₃C—, HOCH₂—, NC—, H₂N—C(═O)—, H₃C—NH—C(═O)—, (H₃C)₂N—C(═O)—, HO—, H₃C—O—, cyclopropyl-H₂C—O—, F₃C—O—, cyclopropyl-O—,

wherein the asterisk (-*) indicates the site/point of attachment.

R¹:

R¹-G1:

The group R¹ is preferably selected from the group R¹-G1 as defined hereinbefore.

R¹-G2:

According to one embodiment the group R¹ is selected from the group R¹-G2 consisting of H, F, Cl, C₁₋₃-alkyl, cyclopropyl, NC—, HO—, and C₁₋₃-alkyl-O—,

-   -   wherein each alkyl group or sub-group within the groups         mentioned under R¹-G2 is optionally substituted with 1 or more F         atoms.

R¹-G3:

According to one embodiment the group R¹ is selected from the group R¹-G3 consisting of H, F, Cl, H₃C—, H₃C—H₂C—, (H₃C)₂HC—, F₃C—, and H₃C—O—.

R¹-G4:

According to one embodiment the group R¹ is selected from the group R¹-G4 consisting of H₃C—.

R²:

R²-G1:

The group R² is preferably selected from the group R²-G1 as defined hereinbefore.

R²-G2:

In another embodiment the group R² is selected from the group R²-G2 consisting of H, F, Cl, H₃C—, F₃C—, NC—, and H₃CO—.

R²-G3:

In another embodiment the group R² is selected from the group R²-G3 consisting of H, F, and F₃C—.

R²-G4:

In another embodiment the group R² is selected from the group R²-G4 consisting of H.

R²-G5:

In another embodiment the group R² is selected from the group R²-G5 consisting of F.

R²-G6:

In another embodiment the group R² is selected from the group R²-G5 consisting of F₃C—.

R³:

R³-G1:

The group R³ is preferably selected from the group R³-G1 as defined hereinbefore.

R³-G2:

In another embodiment the group R³ is selected from the group R³-G2 consisting of of H, F, Cl, H₃C—, NC—, and H₃CO—.

R³-G3:

In another embodiment the group R³ is selected from the group R³-G3 consisting of H.

R^(N):

R^(N)-G1:

The group R^(N) is preferably selected from the group R^(N)-G1 as defined hereinbefore.

R^(N)-G2:

In another embodiment the group R^(N) is selected from the group R^(N)-G2 consisting of H, C₁₋₃-alkyl, HO—C₁₋₄-alkyl-H₂C—, H₃C—O—C₁₋₄-alkyl-, C₁₋₃-alkyl-C(═O)—, and C₁₋₃-alkyl-S(═O)₂—.

R^(N)-G3:

In another embodiment the group R^(N) is selected from the group R^(N)-G3 consisting of H, H₃C—, HO—C₃-alkyl-H₂C—, H₃C—C(═O)—, and H₃C—S(═O)₂—.

m:

m is an integer selected from 1, 2, 3 and 4.

Preferably, m is an integer selected from 1 and 2.

More preferably, m is 2.

n:

n is an integer selected from 1, 2 and 3.

Preferably, n is an integer selected from 1 and 2.

More preferably, n is 1.

The following preferred embodiments of compounds of the formula I are described using generic formulae I.1, I.2, I.3, I.4, I.5, and I.6, wherein any tautomers, solvates, hydrates and salts thereof, in particular the pharmaceutically acceptable salts thereof, are encompassed.

Examples of preferred subgeneric embodiments (E) according to the present invention are set forth in the following Table 1, wherein each substituent group of each embodiment is defined according to the definitions set forth hereinbefore and wherein all other substituents of the formulae I, I.1, I.2, I.3, I.4, I.5, and I.6 are defined according to the definitions set forth hereinbefore. For example, the entry -G1 in the column under R— and in the line of E1 means that in embodiment E1 substituent R is selected from the definition designated R-G1. The same applies analogously to the other variables incorporated in the general formulae.

TABLE 1 E R- R¹- R²- R³- R^(N)- m n E1 -G1 -G1 -G1 -G1 -G1 1, 2, 3, 4 1, 2, 3 E2 -G1 -G1 -G1 -G2 -G2 1, 2 1, 2 E3 -G1 -G1 -G1 -G3 -G3 1, 2 1, 2 E4 -G1 -G1 -G2 -G3 -G3 1, 2 1, 2 E5 -G1 -G2 -G2 -G3 -G1 1, 2 1, 2 E6 -G1 -G2 -G2 -G2 -G2 1, 2 1, 2 E7 -G1 -G2 -G2 -G3 -G3 1, 2 1, 2 E8 -G2 -G1 -G1 -G1 -G1 1, 2 1, 2 E9 -G3 -G1 -G1 -G1 -G1 1, 2 1, 2 E10 -G3 -G1 -G2 -G2 -G2 1, 2 1, 2 E11 -G3 -G2 -G2 -G2 -G2 1, 2 1, 2 E12 -G2 -G2 -G2 -G3 -G3 1, 2 1, 2 E13 -G3 -G2 -G2 -G3 -G3 1, 2 1, 2 E14 -G1 -G3 -G2 -G3 -G3 1, 2 1, 2 E15 -G1 -G2 -G3 -G3 -G3 1, 2 1, 2 E16 -G1 -G3 -G3 -G3 -G3 1, 2 1, 2 E17 -G1 -G4 -G3 -G3 -G3 1, 2 1, 2 E18 -G2 -G3 -G2 -G3 -G3 1, 2 1, 2 E19 -G2 -G2 -G3 -G3 -G3 1, 2 1, 2 E20 -G2 -G3 -G3 -G3 -G3 1, 2 1, 2 E21 -G2 -G4 -G3 -G3 -G3 1, 2 1, 2 E22 -G3 -G3 -G2 -G3 -G3 1, 2 1, 2 E23 -G3 -G2 -G3 -G3 -G3 1, 2 1, 2 E24 -G3 -G3 -G3 -G3 -G3 1, 2 1, 2 E25 -G3 -G4 -G3 -G3 -G3 1, 2 1, 2 E26 -G4 -G3 -G2 -G3 — 2 1, 2 E27 -G4 -G2 -G3 -G3 — 2 1 E28 -G4 -G3 -G3 -G3 — 2 1 E29 -G4 -G4 -G3 -G3 — 2 1 E30 -G5 -G3 -G2 -G3 — 2 1, 2 E31 -G5 -G2 -G3 -G3 — 2 1 E32 -G5 -G3 -G3 -G3 — 2 1 E33 -G5 -G4 -G3 -G3 — 2 1

Another embodiment concerns those compounds of formula I, wherein

R is selected from the group consisting of

H, F, Cl, NC—, H₂NC(═O)—, H₃CHN—C(═O)—, (H₃C)₂N—C(═O)—, HO—;

C₁₋₃-alkyl optionally substituted with 1 or more F or optionally monosubstituted with HO—;

cyclopropyl optionally monosubstituted with NC—;

H₃C—O— optionally monosubstituted with C₁₋₄-alkyl, HOOC—, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, or phenyl,

-   -   wherein the C₁₋₄-alkyl group optionally attached to H₃C—O— is         optionally monosubstituted with NC—, or HO—, and     -   wherein said oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,         tetrahydrothiopyranyl and 1,1-dioxotetrahydrothiopyranyl groups         are optionally monosubstituted with H₃C— or HO—;

cyclopropyl-H₂C—O—, cyclopropyl-O—, tetrahydrofuranyl-O— and tetrahydropyranyl-O—; and

-   -   a heteroaryl group selected from pyrazolyl, [1,2,4]oxadiazolyl,         tetrazolyl, pyridyl, pyridin-2-onyl, pyrazinyl, pyrimidinyl,         pyrimidin-2-onyl, and pyrimidin-4-onyl,     -   wherein each of said heteroaryl groups is optionally         monosubstituted with H₃C—, and     -   wherein each H—N group in said heteroaryl groups is optionally         replaced with H₃C—N or (H₃C)₂C(OH)—H₂C—N,

and 2-methoxypyridin-4-yl;

R¹ is selected from the group consisting of H, F, Cl, H₃C—, H₃C—H₂C—, (H₃C)₂HC—, F₃C—, and H₃C—O—;

m is 2;

R² is selected from the group consisting of H, F, and F₃C—;

n is 1 or 2; and

R³ is selected from the group consisting of H.

Another embodiment concerns those compounds of formula I, wherein

R is selected from the group consisting of

H, F, Cl, H₃C—, H₃C—H₂C—, (H₃C)₂CH—,

F₃C—, HOCH₂—, NC—, H₂N—C(═O)—, H₃C—NH—C(═O)—, (H₃C)₂N—C(═O)—, HO—, H₃C—O—, cyclopropyl-H₂C—O—, F₃C—O—, cyclopropyl-O—,

wherein the asterisk (-*) indicates the site/point of attachment;

R¹ is selected from the group consisting of H₃C—;

m is 2;

R² is selected from the group consisting of H, F, and F₃C—;

n is 1 or 2; and

R³ is selected from the group consisting of H.

Particularly preferred compounds, including their tautomers and stereoisomers, the salts thereof, or any solvates or hydrates thereof, are described in the experimental section hereinafter.

The compounds according to the invention and their intermediates may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis for example using methods described in “Comprehensive Organic Transformations”, 2^(nd) Edition, Richard C. Larock, John Wiley & Sons, 2010, and “March's Advanced Organic Chemistry”, 7^(th) Edition, Michael B. Smith, John Wiley & Sons, 2013. Preferably, the compounds are obtained analogously to the methods of preparation explained more fully hereinafter, in particular as described in the experimental section. In some cases the sequence adopted in carrying out the reaction schemes may be varied. Variants of these reactions that are known to the skilled man but are not described in detail here may also be used. The general processes for preparing the compounds according to the invention will become apparent to the skilled man on studying the schemes that follow. Starting compounds are commercially available or may be prepared by methods that are described in the literature or herein, or may be prepared in an analogous or similar manner. Before the reaction is carried out any corresponding functional groups in the compounds may be protected using conventional protecting groups. These protecting groups may be cleaved again at a suitable stage within the reaction sequence using methods familiar to the skilled man and described in the literature for example in “Protecting Groups”, 3^(rd) Edition, Philip J. Kocienski, Thieme, 2005, and “Protective Groups in Organic Synthesis”, 4^(th) Edition, Peter G. M. Wuts, Theodora W. Greene, John Wiley & Sons, 2006.

The compounds of the invention I are preferably accessed from a precursor II that bears the carboxylic acid function in a protected or masked form as sketched in Scheme 1; R, R¹, R², R³, m and n have the meanings as defined hereinbefore and hereinafter. Suited precursor groups for the carboxylic acid may be, e.g., a carboxylic ester, a carboxylic amide, cyano, an olefin, an oxazole, or a thiazole. All these groups have been transformed into the carboxylic acid function by different means which are described in the organic chemistry literature and are known to the one skilled in the art. The preferred precursor group is a C₁₋₄-alkyl or benzyl carboxylate, each of which may be additionally mono- or polysubstituted with fluorine, methyl, and/or methoxy. These ester groups may be hydrolyzed with an acid, such as hydrochloric acid or sulfuric acid, or an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, to yield the carboxylic acid function; the hydrolysis is preferably conducted in aqueous solvents, such as water and tetrahydrofuran, 1,4-dioxane, alcohol, e.g., methanol, ethanol, and isopropanol, or dimethyl sulfoxide, at 0 to 120° C. A tert-butyl ester is preferably cleaved under acidic conditions with, e.g., trifluoroacetic acid or hydrochloric acid, in a solvent such as dichloromethane, 1,4-dioxane, isopropanol, or ethyl acetate. A benzyl ester is advantageously cleaved using hydrogen in the presence of a transition metal, preferably palladium on carbon. Benzyl esters bearing electron donating groups, such as methoxy, on the aromatic ring may also be removed under oxidative conditions; ceric ammonium nitrate (CAN) or 2,3-dichloro-5,6-dicyanoquinone (DDQ) are two commonly used reagents for this approach. The carboxylic acid group may also be introduced at an earlier stage of the synthesis, e.g., prior to the coupling of the pyridine part with the benzyl amino residue or the C—C coupling of the two phenyl subgroups as described in the experimental section.

Compound II, in turn, may be obtained from benzylamine III and pyridine IV which bears the carboxylic acid group or a precursor group thereof and a leaving group (Scheme 2); R, R¹, R², R³, m and n in Scheme 2 have the meanings as defined hereinbefore and hereinafter. The leaving group LG in IV is replaced with the NH group in III via a nucleophilic substitution reaction on the pyridine ring; suited LG may be F, Cl, Br, and I. The reaction is usually carried out in the presence of a base, such as triethylamine, ethyldiisopropylamine, 1,8-diazabicyclo[5.4.0]undecene, carbonates, e.g., Li₂CO₃, Na₂CO₃, K₂CO₃, and Cs₂CO₃, hydroxides, e.g., LiOH, NaOH, and KOH, alcoholates, e.g., NaOMe, NaOEt, and KOtBu, and oxides, e.g., CaO and Ag₂O. Additives, such as silver salts, e.g., AgNO₃, AgOSO₂CF₃, and Ag₂CO₃, may be beneficial or essential for the reaction to proceed. Preferred solvents are dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, acetonitrile, 1,4-dioxane, tetrahydrofuran, alcohol, e.g., ethanol or isopropanol, water, or mixtures thereof at temperatures of 20 to 220° C.

Preferably, coupling of benzylamine III and pyridine IV is mediated by a transition metal catalyst. Suited pyridines IV for this approach bear Cl, Br, or I as LG, and the catalyst is preferably derived from Cu, Ni, and Pd. The catalyst or the precursor thereof may be a complex of the transition metal with ligands such as phosphines, e.g. tri-tert-butylphosphine, tricyclohexylphosphine, optionally substituted biphenyl-dicyclohexylphosphines, optionally substituted biphenyl-di-tert-butylphosphines, 1,1′-bis(diphenylphosphino)ferrocene, triphenylphosphine, tritolylphosphine, Xantphos, or trifurylphosphine, phosphites, 1,3-disubstituted imidazole carbenes, 1,3-disubstituted imidazolidine carbenes, oxalamides, dibenzylideneacetone, allyl, or nitriles, an elemental form of the transition metal such as palladium on carbon or nanoparticles of palladium, or a salt of the transition metal such as fluoride, chloride, bromide, acetate, triflate, acetylacetonate, or trifluoroacetate that may be combined with a separately added ligand. The reaction is preferably conducted in the presence of a base such as an alcoholate, e.g., LiOtBu, NaOtBu, KOtBu, and KOtPent, alcoholate, a hydroxide, e.g., LiOH, NaOH, and KOH, lithium hexamethyldisilazide, K₃PO₄, carbonate such as Cs₂CO₃, or phenolate such as sodium 2,6-di-tert-butyl-4-methyl-phenolate. The coupling reactions are preferably conducted in benzene, toluene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, alcohol such as tBuOH or tPentOH, water, or mixtures thereof, at temperatures in the range of 20 to 180° C.

Compounds of general structure IV wherein R³ has the meaning as defined hereinbefore and hereinafter and CP is a suitable carboxylic acid ester group can be synthesized as summarized in Scheme 3.

Cinnamic acid ester VII is reacted with a methylene synthetic equivalent to give ester IV′. Suitable reagents for this transformation include diazomethane in the presence of a transition metal catalyst such as palladium diacetate (see, e.g., WO2011/94890), trimethyloxosulfonium halide in the presence of a base such as sodium hydride (see, e.g., WO2005/103032), and diiodomethane in the presence of copper and zinc (see, e.g., U.S. Pat. No. 628,476). Generally, use of a trans-cinnamic acid ester in these reactions leads to predominant formation of a trans-substituted cyclopropyl ester. Enantioselective variants of this type of reaction are reported in the literature such as the one using diazomethane and chiral copper complexes (see, e.g., Tetrahedron Asymmetry 2003, 14, 867-872).

Alternatively, pyridine IV′ is obtained from vinylpyridine VIII and diazoacetic ester IX in the presence of a transition metal catalyst. Suitable catalyst systems for this transformation include, for example, palladium diacetate (see, e.g., WO2007/104717), cobalt(II) porphyrins (see, e.g., WO2006/103503), rhodium complexes (see, e.g., WO2006/87169), and copper complexes (see, e.g., WO2010/51819). Mixtures of cis- and trans-cyclopropyl esters are generally formed with the trans-system predominant and the ratio depending on the catalyst system and substrates used. Enantioselective reactions of this type are reported using chiral transition metal catalysts derived from copper and cobalt (see, e.g., J. Am. Chem Soc. 1991, 113, 726-728) and variations thereof.

Alternatively, compounds of general structure II may be accessed as described in the experimental section (Scheme 4). Starting form pyridine X compound XI is synthesized via a transition metal catalyzed coupling reaction using preferably a Pd catalyst with a carbamate, e.g., tert-butylcarbamic acid. Product XI is then alkylated with a benzyl halide or pseudohalide XII, that bears an additional leaving group on the phenyl ring such as bromine for further derivatization, in the presence of a base, e.g., sodium hydride, to give compound XIII. Compound XIII may be coupled with boronic acids XIV or boronic esters thereof using a transition metal catalyst, preferably a Pd derived catalyst, to provide compounds II′. The reactivity of the two coupling partners XIII and XIV may be reversed, i.e. compound XIII is employed as the nucleophilic and compound XIV as the electrophilic partner, to provide compounds II′ under analogous reaction conditions. For this purpose compound XIII bearing a bromine atom is transformed into the corresponding boronic acid or ester employing a diboron species and a Pd catalyst.

The synthetic routes presented may rely on the use of protecting groups. For example, potentially reactive groups present, such as hydroxy, carbonyl, carboxy, amino, alkylamino, or imino, may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction. Suitable protecting groups for the respective functionalities and their removal are well known to the one skilled in the art and are described in the literature of organic synthesis for example in “Protecting Groups”, 3^(rd) Edition, Philip J. Kocienski, Thieme, 2005, or “Protective Groups in Organic Synthesis”, 4th Edition, Peter G. M. Wuts, Theodora W. Greene, John Wiley & Sons, 2006.

The compounds of general formula I may be resolved into their enantiomers and/or diastereomers as mentioned below. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers and racemic compounds may be separated into their enantiomers.

The cis/trans mixtures may be resolved, for example, by chromatography into the cis and trans isomers thereof. The compounds of general formula I which occur as racemates may be separated by methods known per se into their optical antipodes and diastereomeric mixtures of compounds of general formula I may be resolved into their diastereomers by taking advantage of their different physico-chemical properties using methods known per se, e.g. chromatography and/or fractional crystallization; if the compounds obtained thereafter are racemates, they may be resolved into the enantiomers as mentioned below.

The racemates are preferably resolved by column chromatography on chiral phases or by crystallization from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as esters or amides with the racemic compound. Salts may be formed with enantiomerically pure acids for basic compounds and with enantiomerically pure bases for acidic compounds. Diastereomeric derivatives are formed with enantiomerically pure auxiliary compounds, e.g. acids, their activated derivatives, or alcohols. Separation of the diastereomeric mixture of salts or derivatives thus obtained may be achieved by taking advantage of their different physico-chemical properties, e.g. differences in solubility; the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids commonly used for such a purpose as well as optically active alcohols applicable as auxiliary residues are known to those skilled in the art.

As mentioned above, the compounds of formula I may be converted into salts, particularly for pharmaceutical use into the pharmaceutically acceptable salts. As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.

The compounds according to the invention are advantageously also obtainable using the methods described in the examples that follow, which may also be combined for this purpose with methods known to the skilled man from the literature.

Terms and Definitions

Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

The terms “compound(s) according to this invention”, “compound(s) of formula (I)”, “compound(s) of the invention” and the like denote the compounds of the formula (I) according to the present invention including their tautomers, stereoisomers and mixtures thereof and the salts thereof, in particular the pharmaceutically acceptable salts thereof, and the solvates and hydrates of such compounds, including the solvates and hydrates of such tautomers, stereoisomers and salts thereof.

The terms “treatment” and “treating” embrace both preventative, i.e. prophylactic, or therapeutic, i.e. curative and/or palliative, treatment. Thus the terms “treatment” and “treating” comprise therapeutic treatment of patients having already developed said condition, in particular in manifest form. Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of the specific indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow down progression of the disease. Thus the compositions and methods of the present invention may be used for instance as therapeutic treatment over a period of time as well as for chronic therapy. In addition the terms “treatment” and “treating” comprise prophylactic treatment, i.e. a treatment of patients at risk to develop a condition mentioned hereinbefore, thus reducing said risk.

When this invention refers to patients requiring treatment, it relates primarily to treatment in mammals, in particular humans.

The term “therapeutically effective amount” means an amount of a compound of the present invention that (i) treats or prevents the particular disease or condition, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease or condition, or (iii) prevents or delays the onset of one or more symptoms of the particular disease or condition described herein.

The terms “modulated” or “modulating”, or “modulate(s)”, as used herein, unless otherwise indicated, refer to the activation of the G-protein-coupled receptor GPR40 with one or more compounds of the present invention.

The terms “mediated” or “mediating” or “mediate”, as used herein, unless otherwise indicated, refer to the (i) treatment, including prevention of the particular disease or condition, (ii) attenuation, amelioration, or elimination of one or more symptoms of the particular disease or condition, or (iii) prevention or delay of the onset of one or more symptoms of the particular disease or condition described herein.

The term “substituted” as used herein, means that any one or more hydrogens on the designated atom, radical or moiety is replaced with a selection from the indicated group, provided that the atom's normal valence is not exceeded, and that the substitution results in an acceptably stable compound.

In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C₁₋₆-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, for groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent “aryl-C₁₋₃-alkyl-” means an aryl group which is bound to a C₁₋₃-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.

In case a compound of the present invention is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail.

An asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.

The numeration of the atoms of a substituent starts with the atom which is closest to the core or to the group to which the substituent is attached.

For example, the term “3-carboxypropyl-group” represents the following substituent:

wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or “cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.

In a definition of a group the term “wherein each X, Y and Z group is optionally substituted with” and the like denotes that each group X, each group Y and each group Z either each as a separate group or each as part of a composed group may be substituted as defined. For example a definition “R^(ex) denotes H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl or C₁₋₃-alkyl-O—, wherein each alkyl group is optionally substituted with one or more L^(ex).” or the like means that in each of the beforementioned groups which comprise the term alkyl, i.e. in each of the groups C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl and C₁₋₃-alkyl-O—, the alkyl moiety may be substituted with L^(ex) as defined.

Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc. . . . ) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.

Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts) also comprise a part of the invention.

The term halogen generally denotes fluorine, chlorine, bromine and iodine.

The term “C_(1-n)-alkyl”, wherein n is an integer from 1 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—, H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—, H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—, H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—, H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— and H₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(1-n)-alkylene” wherein n is an integer 1 to n, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms. For example the term C₁₋₄-alkylene includes —(CH₂)—, —(CH₂—CH₂)—, —(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—, —(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—, —(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—, —(CH₂—C(CH₃)₂—, —C(CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—, —(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—, —(CHCH(CH₃)₂)— and —C(CH₃)(CH₂CH₃)—.

The term “C_(2-n)-alkenyl”, is used for a group as defined in the definition for “C_(1-n)-alkyl” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a double bond. For example the term C₂₋₃-alkenyl includes —CH═CH₂, —CH═CH—CH₃, —CH₂—CH═CH₂.

The term “C_(2-n)-alkynyl”, is used for a group as defined in the definition for “C_(1-n)-alkyl” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a triple bond. For example the term C₂₋₃-alkynyl includes —C≡CH, —C≡C—CH₃, —CH₂—C≡CH.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer 4 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms. The cyclic group may be mono-, bi-, tri- or spirocyclic, most preferably monocyclic. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.

Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.

Pharmacological Activity

The activity of the compounds of the invention may be demonstrated using the following assay:

IP₁ accumulation measurements using the IPOne assay system—1321N1 cells stably expressing human GPR40 receptor (Euroscreen, Belgium) are seeded 24 h before the assay in white 384-well plates in culture medium containing 10% FCS, 1% Na-Pyruvate and 400 μg/mL G418. IPi is assayed according to the manufacturer's description (Cisbio Bioassays, France). In brief, the assay is started by substitution of the culture medium by stimulation buffer (Hepes 10 mM, CaCl₂ 1 mM, MgCl₂ 0.5 mM, KCl 4.2 mM, NaCl 146 mM, glucose 5.5 mM and LiCl 50 mM, pH 7.4). Cells are stimulated for 1 h at 37° C., 5% CO₂ by addition of the compounds that are diluted in stimulation buffer containing LiCl. Assays are stopped by adding HTRF-conjugates (IP1-d2 and Anti-IP1 cryptate Tb) and lysis buffer, provided by the manufacturer. After an incubation time of 1 h at room temperature plates are measured using an EnVision™, Perkin Elmer. The obtained fluorescence ratios at 665/615 nM are then used to calculate the pEC₅₀ values using Assay Explorer 3.3 Software (Accelrys, Inc.) by interpolation using an IP₁ reference curve and subsequent sigmoidal curve fitting allowing for a variable hill slope.

The compounds according to the invention typically have EC₅₀ values in the range from about 1 nM to about 10 μM, preferably less than 1 μM, more preferably less than 100 nM.

EC₅₀ values for compounds according to the invention are shown in the following table. The number of the compound corresponds to the number of the Example in the experimental section.

TABLE 2 Exam- EC₅₀ Exam- EC₅₀ Exam- EC₅₀ Exam- EC₅₀ ple [nM] ple [nM] ple [nM] ple [nM] 1 45 2 42 3 >10000 4 15 5 12 6 38 7 34 8 50 9 256 10 22 11 21 12 >10000 13 17 14 11 15 26 16 64 17 353 18 131 19 2097 20 2295 21 834 22 477 23 >10000 24 204 25 41 26 79 27 >10000 28 6725 29 570 30 877 31 105 32 1944 33 128 34 612 35 137 36 85 37 63 38 94 39 1444 40 443 41 81 42 100 43 54 44 32 45 147 46 96 47 107 48 20 49 72 50 25 51 106 52 1344 53 15 54 317 55 220 56 12 57 422 58 43 59 375 60 550 61 36 62 668 63 931 64 123 65 >10000 66 48 67 31 68 59 69 5964 70 3629 71 140 72 838 73 40 74 1338 75 50 76 340 77 83 78 5 79 42 80 59 81 491 82 236 83 104 84 57 85 25 86 29 87 89 88 81 89 65 90 8 91 43 92 16 93 72 94 1319 95 11 96 114 97 189 98 102 99 8 100 101 101 39 102 420 103 462

Chemical Stability

Degradation kinetics is used to simulate chemical stability of compounds in the acidic part of the gastro intestinal tract. The compounds of the invention show superior chemical stability in acidic aqueous media (pH value ca. 1.2) compared to the bulk of compounds explicitly disclosed in WO 2013/178575. Their application as medical drugs to treat human diseases is therefore less restricted and troublesome.

The chemical stability of the compounds of the invention at pH value of ca. 1.2 is determined as follows:

Compound is dissolved in an HPLC vial either in a mixture of acetonitrile/0.1 M aqueous HCl (2:3; pH ca. 1.2) or in a mixture of acetonitrile/Mcllvaine buffer pH 7.4 (2:3) to get a concentration of approximately 0.25 mg/ml. The vial was then transferred into an HPLC autosampler system and maintained at a temperature of 37° C. A first sample is taken and injected immediately into a standard HPLC system with a UV DAD detector. Further samples are injected after 2, 4, 6, 8 and 10 hours. Amount of degraded compound is measured by determining the recovery rate of compound [%] for each injection using an HPLC standard gradient method. Therefore the peak area of the main peak for the first injection (AU_(t0)) is determined and set as 100%. Peak area of the main peak is determined also for the further injections (AU_(tn, n=2, 4, 6, 8, 10)) and expressed as fraction of (AU_(t0))/(AU_(tn, n=2, 4, 6, 8, 10)) [%].

The amount of degraded compound according to the invention after 2 h at pH value of ca. 1.2 determined as described above is typically below 0.5%.

The following table compares the amount of degradation after 2 h at pH value of ca. 1.2 of compounds according to the invention and compounds from WO 2013/178575 (for structures see below Table 3).

TABLE 3 Amount of Amount of Example in this degradation Example in degradation invention after 2 h WO 2013/178575 after 2 h 4 <0.5% 17 8% 18 <0.5% 33 8% 48 <0.5% 11 5% 15 3% 54 2.5%  

Chemical structures of the examples from case WO 2013/178575 listed in the tables 3 and 4:

Solubility

The aqueous solubility of the compounds of the invention is determined by comparing the amount dissolved in buffer to the amount in an acetonitrile/water (1/1) solution. Starting from a 10 mM DMSO stock solution aliquots are diluted with acetonitrile/water (1/1) or buffer, respectively. After 24 h of shaking, the solutions are filtrated and analyzed by LC-UV. The amount dissolved in buffer is compared to the amount in the acetonitrile solution.

Solubility is usually being measured from 0.001 to 0.125 mg/mL at a DMSO concentration of 2.5%. If more than 90% of the compound is dissolved in buffer, the value is marked with “>”.

The compounds of the invention show higher solubility at low pH value (pH 2.2, emulating the acidic part of the gastro intestinal tract) compared with the bulk of compounds explicitly disclosed in WO 2013/178575. Their development and application is therefore more convenient and reliable. The following table presents the data for selected compounds of this invention and compounds from WO 2013/178575 (for structures see above below Table 3).

TABLE 4 Solubility at pH Solubility at pH Example in this value 2.2 Example in value 2.2 invention [μg/mL] WO 2013/178575 [μg/mL] 1 87 15 <1 2 83 17 <1 4 92 45 <1 7 30 54 <1 18 >120 25 83 26 91 30 112 35 86 38 99 42 87 43 107 48 102 53 78 55 122 56 96 61 42 67 84 68 >120 77 97 80 106 90 89 92 103 93 82 95 88 97 123 99 97

In view of their ability to modulate the activity of the G-protein-coupled receptor GPR40, in particular an agonistic activity, the compounds of general formula I according to the invention, including the corresponding salts thereof, are theoretically suitable for the treatment of all those diseases or conditions which may be affected or which are mediated by the activation of the G-protein-coupled receptor GPR40.

Accordingly, the present invention relates to a compound of general formula I as a medicament.

Furthermore, the present invention relates to the use of a compound of general formula I or a pharmaceutical composition according to this invention for the treatment and/or prevention of diseases or conditions which are mediated by the activation of the G-protein-coupled receptor GPR40 in a patient, preferably in a human.

In yet another aspect the present invention relates to a method for treating a disease or condition mediated by the activation of the G-protein-coupled receptor GPR40 in a mammal that includes the step of administering to a patient, preferably a human, in need of such treatment a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.

Diseases and conditions mediated by agonists of the G-protein-coupled receptor GPR40 embrace metabolic diseases or conditions. According to one aspect the compounds and pharmaceutical compositions of the present invention are particularly suitable for treating diabetes mellitus, in particular Type 2 diabetes, Type 1 diabetes, complications of diabetes (such as e.g. retinopathy, nephropathy or neuropathies, diabetic foot, ulcers or macroangiopathies), metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, oedema and hyperuricaemia.

The compounds and pharmaceutical compositions of the present invention are also suitable for preventing beta-cell degeneration such as e.g. apoptosis or necrosis of pancreatic beta cells. The compounds and pharmaceutical compositions of the present invention are also suitable for improving or restoring the functionality of pancreatic cells, and also for increasing the number and size of pancreatic beta cells.

Therefore according to another aspect the invention relates to compounds of formula I and pharmaceutical compositions according to the invention for use in preventing, delaying, slowing the progression of and/or treating metabolic diseases, particularly in improving the glycaemic control and/or beta cell function in the patient.

In another aspect the invention relates to compounds of formula I and pharmaceutical compositions according to the invention for use in preventing, delaying, slowing the progression of and/or treating type 2 diabetes, overweight, obesity, complications of diabetes and associated pathological conditions.

In addition the compounds and pharmaceutical compositions according to the invention are suitable for use in one or more of the following therapeutic processes:

for preventing, delaying, slowing the progression of or treating metabolic diseases, such as for example type 1 diabetes, type 2 diabetes, insufficient glucose tolerance, insulin resistance, hyperglycaemia, hyperlipidaemia, hypercholesterolaemia, dyslipidaemia, syndrome X, metabolic syndrome, obesity, high blood pressure, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, endothelial dysfunction or bone-related diseases (such as osteoporosis, rheumatoid arthritis or osteoarthritis);

for improving glycaemic control and/or reducing fasting plasma glucose, postprandial plasma glucose and/or the glycosylated haemoglobin HbA1c;

for preventing, delaying, slowing or reversing the progression of disrupted glucose tolerance, insulin resistance and/or metabolic syndrome to type 2 diabetes;

for preventing, delaying, slowing the progression of or treating a condition or a disease selected from among the complications of diabetes, such as for example retinopathy, nephropathy or neuropathies, diabetic foot, ulcers or macroangiopathies;

for reducing weight or preventing weight gain or assisting weight loss;

for preventing or treating the degradation of pancreatic beta cells and/or improving and/or restoring the functionality of pancreatic beta cells and/or restoring the functionality of pancreatic insulin secretion;

for maintaining and/or improving insulin sensitivity and/or preventing or treating hyperinsulinaemia and/or insulin resistance.

In particular, the compounds and pharmaceutical compositions according to the invention are suitable for the treatment of obesity, diabetes (comprising type 1 and type 2 diabetes, preferably type 2 diabetes mellitus) and/or complications of diabetes (such as for example retinopathy, nephropathy or neuropathies, diabetic foot, ulcers or macroangiopathies).

The compounds according to the invention are most particularly suitable for treating type 2 diabetes mellitus.

The dose range of the compounds of general formula I applicable per day is usually from 0.001 to 10 mg per kg body weight, for example from 0.01 to 8 mg per kg body weight of the patient. Each dosage unit may conveniently contain from 0.1 to 1000 mg, for example 0.5 to 500 mg.

The actual therapeutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the compound or composition will be administered at dosages and in a manner which allows a therapeutically effective amount to be delivered based upon patient's unique condition.

The compounds, compositions, including any combinations with one or more additional therapeutic agents, according to the invention may be administered by oral, transdermal, inhalative, parenteral or sublingual route. Of the possible methods of administration, oral or intravenous administration is preferred.

Pharmaceutical Compositions

Suitable preparations for administering the compounds of formula I, optionally in combination with one or more further therapeutic agents, will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders etc. Oral formulations, particularly solid forms such as e.g. tablets or capsules are preferred. The content of the pharmaceutically active compound(s) is advantageously in the range from 0.1 to 90 wt.-%, for example from 1 to 70 wt.-% of the composition as a whole.

Suitable tablets may be obtained, for example, by mixing one or more compounds according to formula I with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants. The tablets may also consist of several layers. The particular excipients, carriers and/or diluents that are suitable for the desired preparations will be familiar to the skilled man on the basis of his specialist knowledge. The preferred ones are those that are suitable for the particular formulation and method of administration that are desired. The preparations or formulations according to the invention may be prepared using methods known per se that are familiar to the skilled man, such as for example by mixing or combining at least one compound of formula I according to the invention, or a pharmaceutically acceptable salt of such a compound, and one or more excipients, carriers and/or diluents.

Combination Therapy

The compounds of the invention may further be combined with one or more, preferably one additional therapeutic agent. According to one embodiment the additional therapeutic agent is selected from the group of therapeutic agents useful in the treatment of diseases or conditions described hereinbefore, in particular associated with metabolic diseases or conditions such as for example diabetes mellitus, obesity, diabetic complications, hypertension, hyperlipidemia. Additional therapeutic agents which are suitable for such combinations include in particular those which for example potentiate the therapeutic effect of one or more active substances with respect to one of the indications mentioned and/or which allow the dosage of one or more active substances to be reduced.

Therefore a compound of the invention may be combined with one or more additional therapeutic agents selected from the group consisting of antidiabetic agents, agents for the treatment of overweight and/or obesity and agents for the treatment of high blood pressure, heart failure and/or atherosclerosis.

Antidiabetic agents are for example metformin, sulphonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-(alpha, gamma or alpha/gamma) agonists or modulators, alpha-glucosidase inhibitors, DPPIV inhibitors, SGLT2-inhibitors, insulin and insulin analogues, GLP-1 and GLP-1 analogues or amylin and amylin analogues, cycloset, 11β-HSD inhibitors. Other suitable combination partners are inhibitors of protein tyrosinephosphatase 1, substances that affect deregulated glucose production in the liver, such as e.g. inhibitors of glucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, alpha2-antagonists, CCR-2 antagonists or glucokinase activators. One or more lipid lowering agents are also suitable as combination partners, such as for example HMG-CoA-reductase inhibitors, fibrates, nicotinic acid and the derivatives thereof, PPAR-(alpha, gamma or alpha/gamma) agonists or modulators, PPAR-delta agonists, ACAT inhibitors or cholesterol absorption inhibitors such as, bile acid-binding substances such as, inhibitors of ileac bile acid transport, MTP inhibitors, or HDL-raising compounds such as CETP inhibitors or ABC1 regulators.

Therapeutic agents for the treatment of overweight and/or obesity are for example antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists, β3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor.

Therapeutic agents for the treatment of high blood pressure, chronic heart failure and/or atherosclerosis are for example A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, β-blockers, Ca-antagonists, centrally acting antihypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable. Angiotensin II receptor antagonists are preferably used for the treatment or prevention of high blood pressure and complications of diabetes, often combined with a diuretic such as hydrochlorothiazide.

The dosage for the combination partners mentioned above is usually ⅕ of the lowest dose normally recommended up to 1/1 of the normally recommended dose.

Preferably, compounds of the present invention and/or pharmaceutical compositions comprising a compound of the present invention optionally in combination with one or more additional therapeutic agents are administered in conjunction with exercise and/or a diet.

Therefore, in another aspect, this invention relates to the use of a compound according to the invention in combination with one or more additional therapeutic agents described hereinbefore and hereinafter for the treatment of diseases or conditions which may be affected or which are mediated by the activation of the G-protein-coupled receptor GPR40, in particular diseases or conditions as described hereinbefore and hereinafter.

In yet another aspect the present invention relates a method for treating a disease or condition mediated by the activation of the G-protein-coupled receptor GPR40 in a patient that includes the step of administering to the patient, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of one or more additional therapeutic agents described in hereinbefore and hereinafter,

The use of the compound according to the invention in combination with the additional therapeutic agent may take place simultaneously or at staggered times.

The compound according to the invention and the one or more additional therapeutic agents may both be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as a so-called kit-of-parts.

Consequently, in another aspect, this invention relates to a pharmaceutical composition which comprises a compound according to the invention and one or more additional therapeutic agents described hereinbefore and hereinafter, optionally together with one or more inert carriers and/or diluents.

Other features and advantages of the present invention will become apparent from the following more detailed Examples which illustrate, by way of example, the principles of the invention.

EXAMPLES

The terms “ambient temperature” and “room temperature” are used interchangeably and designate a temperature of about 20° C.

As a rule, ¹H-NMR and/or mass spectra have been obtained for the compounds prepared.

Analytical HPLC parameters employed for characterization of products (TFA denotes trifluoroacetic acid and FA denotes formic acid):

Method: 1 Device: Agilent 1200 with DA- and MS-Detector Column: XBridge C18, 3 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ Solvent Time % Solvent % Solvent Flow Temperature [min] [H₂O, 0.1% TFA] [Acetonitrile] [ml/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

Method: 2 Device Agilent 1200 with DA- and MS-Detector Column: Sunfire C18, 3 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ Solvent Time % Solvent % Solvent Flow Temperature [min] [H₂O, 0.1% TFA] [Acetonitrile] [ml/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

Method: 3 Device Waters Acquity, QDa Detector Column: Sunfire C18_3.0 × 30 mm_2.5 μm Column Supplier: Waters Gradient/ Solvent Time % Solvent % Solvent Flow Temperature [min] [H₂O, 0.1% TFA] [Acetonitrile] [ml/min] [° C.] 0.0 95.0 5.0 1.5 60.0 1.3 0.0 100.0 1.5 60.0 1.5 0.0 100.0 1.5 60.0 1.6 95.0 5.0 1.5 60.0 0.0 95.0 5.0 1.5 60.0

Method: 4 Device Waters Acquity, QDa Detector Column: XBridge C18_3.0 × 30 mm_2.5 μm Column Supplier: Waters Gradient/ Solvent Time % Solvent % Solvent Flow Temperature [min] [H₂O, 0.1% TFA] [Acetonitrile] [ml/min] [° C.] 0.0 95.0 5.0 1.5 60.0 1.3 0.0 100.0 1.5 60.0 1.5 0.0 100.0 1.5 60.0 1.6 95.0 5.0 1.5 60.0 0.0 95.0 5.0 1.5 60.0

Intermediate 1 trans-2-(6-Chloro-pyridin-3-yl)-cyclopropanecarboxylic Acid ethyl ester

Step 1: 2-Chloro-5-vinyl-pyridine

Aqueous 2 M Na₂CO₃ solution (50 mL) is added to a flask charged with a stir bar, 2-chloro-5-iodo-pyridine (10.0 g), vinyl boronic acid pinacol ester (7.9 mL), and 1,4-dioxane (100 mL) at room temperature. The mixture is purged with Ar for 5 min prior to the addition of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (1.0 g). The mixture is stirred at 70° C. overnight. After cooling to room temperature, the mixture is concentrated. Ethyl acetate is added to the residue, and the resulting mixture is washed with water and dried (MgSO₄). The solvent is evaporated, and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 7:3→0:1) to give the title compound. Mass spectrum (ESI⁺): m/z=140/142 (Cl) [M+H]⁺.

Alternatively, the title compound is prepared from 2-chloro-pyridine-5-carbaldehyde as described in EP1236723.

Step 2: trans-2-(6-Chloro-pyridin-3-yl)-cyclopropanecarboxylic Acid ethyl ester

5,10,15,20-Tetraphenyl-21H,23H-porphine cobalt(II) (0.5 g), 1-methylimidazole (7.8 g), and ethyl diazoacetate (13% in dichloromethane; 31 mL) are added to a flask charged with a stir bar, 2-chloro-5-vinyl-pyridine (4.4 g), and toluene (50 mL) at room temperature. The mixture is stirred at room temperature for 5 min and then at 80° C. overnight. After cooling to room temperature, the mixture is concentrated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 6:1) to give the racemic trans configured title compound. Mass spectrum (ESI⁺): m/z=226/228 (Cl) [M+H]⁺.

Alternatively, the title compound is obtained from 3-(6-chloro-pyridin-3-yl)-acrylic acid ethyl ester and trimethylsulfoxonium halide as described in EP1741708.

Intermediate 2 and 3 (1R,2R)-2-(6-Chloro-pyridin-3-yl)-cyclopropanecarboxylic Acid ethyl ester and (1S,2S)-2-(6-Chloro-pyridin-3-yl)-cyclopropanecarboxylic Acid ethyl ester

The pure title compounds are obtained from the racemic mixture upon SFC separation on chiral phase (column: Chiralcel AD-H (Daicel Corp.), 5 μm, 250 mm×20 mm; eluent: scCO₂/methanol 90:10, 40° C., 150 bar, 60 mL/min):

(1S,2S)-2-(6-Chloro-pyridin-3-yl)-cyclopropanecarboxylic acid ethyl ester: t_(R)=5.9 min

(1R,2R)-2-(6-Chloro-pyridin-3-yl)-cyclopropanecarboxylic acid ethyl ester: t_(R)=6.8 min.

Alternatively, the racemic mixture is resolved via crystallization of the diastereomeric salts formed upon treatment of the corresponding racemic mixture of carboxylic acids with (R)- or (S)-1-phenethylamine in, e.g., an alcohol such as isopropanol. The carboxylic acids of the 1-phenethylammonium salts are liberated and separated by treatment with hydrochloric acid solution and extraction with ethyl acetate.

Intermediate 4 (1S,2S)-2-(6-tert-Butoxycarbonylamino-pyridin-3-yl)-cyclopropanecarboxylic Acid ethyl ester

A flask charged with a stir bar, tert-butyl carbamate (5.2 g), (1S,2S)-2-(6-chloro-pyridin-3-yl)-cyclopropanecarboxylic acid ethyl ester (2.0 g), Cs₂CO₃ (4.3 g), and 1,4-dioxane (24 mL) is purged with Ar for 10 min. Xantphos (0.4 g) and palladium(II) acetate (0.2 g) are added, the flask is sealed, and the mixture is stirred at 100° C. for 1 h. After cooling to room temperature, aqueous NH₄Cl solution is added, and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (MgSO₄) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 3:1→0:1) to give the title compound. LC (method 1): t_(R)=0.88 min; Mass spectrum (ESI⁺): m/z=307 [M+H]⁺.

Intermediate 5 (1S,2S)-2-{6-[(5-Bromo-2-fluoro-benzyl)-tert-butoxycarbonyl-amino]-pyridin-3-yl}-cyclopropanecarboxylic Acid ethyl ester

Sodium hydride (55% in mineral oil; 0.56 g) is added to a flask charged with a stir bar, (1S,2S)-2-(6-tert-butoxycarbonylamino-pyridin-3-yl)-cyclopropanecarboxylic acid ethyl ester (5.50 g), and N,N-dimethylformamide (15 mL) chilled in an ice bath. The mixture is stirred for 10 min, and then 4-bromo-2-bromomethyl-1-fluoro-benzene (3.57 g; for preparation see J. Med. Chem. 1999, 42, 3572-3587) is added. The ice bath is removed, and the mixture is stirred at room temperature. After 1 h of stirring, aqueous saturated NH₄Cl solution is added, and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are concentrated, and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 9:1→3:2) to give the title compound. LC (method 1): t_(R)=1.27 min; Mass spectrum (ESI⁺): m/z=493/495 (Br) [M+H]⁺.

Intermediate 6 (1S,2S)-2-[6-(5-Bromo-2-fluoro-benzylamino)-pyridin-3-yl]-cyclopropanecarboxylic Acid ethyl ester

Hydrochloric acid (4 mol/L in 1,4 dioxane; 12 mL) is added to a flask charged with a stir bar, (1S,2S)-2-{6-[(5-bromo-2-fluoro-benzyl)-tert-butoxycarbonyl-amino]-pyridin-3-yl}-cyclopropanecarboxylic acid ethyl ester (6.18 g), and 1,4-dioxane (20 mL) at room temperature. The mixture is stirred at room temperature overnight. The mixture is poured slowly into a stirred aqueous K₂CO₃ solution chilled in an ice bath, and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (MgSO₄), and concentrated to give the title compound. LC (method 1): t_(R)=0.88 min; Mass spectrum (ESI⁺): m/z=393/395 (Br) [M+H]⁺.

Intermediate 7 (1S,2S)-2-{6-[2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylamino]-pyridin-3-yl}-cyclopropanecarboxylic Acid ethyl ester

A flask charged with a stir bar, (1S,2S)-2-[6-(5-bromo-2-fluoro-benzylamino)-pyridin-3-yl]-cyclopropanecarboxylic acid ethyl ester (4.88 g), bis(pinacolato)diboron (3.15 g), potassium acetate (2.43 g), and 1,4-dioxane (20 mL) is purged with Ar for 10 min. 1,1′-Bis(diphenylphosphino)ferrocene-dichloropalladium(II) (181 mg) is added, the flask is sealed, and the mixture is stirred at reflux temperature for 1 h. After cooling to room temperature, the mixture is diluted with ether, and aqueous NH₄Cl solution is added. The resulting mixture is extracted with ethyl acetate and the combined organic phase is washed with brine and dried (MgSO₄). The organic phase is concentrated, and the residue is chromatographed on reversed phase (MPLC; MeCN/water/F₃COOH as eluent) to give the title compound. LC (method 1): t_(R)=0.97 min; Mass spectrum (ESI⁺): m/z=441 [M+H]⁺.

Intermediate 8 (1S,2S)-2-{6-[(4-Bromo-2,4-difluoro-benzyl)-tert-butoxycarbonyl-amino]-pyridin-3-yl}-cyclopropanecarboxylic Acid ethyl ester

The title compound is prepared from (1S,2S)-2-(6-tert-butoxycarbonylamino-pyridin-3-yl)-cyclopropanecarboxylic acid ethyl ester and 1-bromo-5-bromomethyl-2,4-difluoro-benzene (for preparation see WO2015/51725) following a procedure analogous to that described for Intermediate 5. LC (method 1): t_(R)=1.25 min; Mass spectrum (ESI⁺): m/z=511/513 (Br) [M+H]⁺.

Intermediate 9 (1S,2S)-2-[6-(4-Bromo-2,4-difluoro-benzylamino)-pyridin-3-yl]-cyclopropanecarboxylic Acid ethyl ester

The title compound is prepared from (1S,2S)-2-{6-[(4-bromo-2,4-difluoro-benzyl)-tert-butoxycarbonyl-amino]-pyridin-3-yl}-cyclopropanecarboxylic acid ethyl ester following a procedure analogous to that described for Intermediate 6. LC (method 1): t_(R)=0.86 min; Mass spectrum (ESI⁺): m/z=411/413 (Br) [M+H]⁺.

Intermediate 10 (1S,2S)-2-{6-[2,4-Difluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylamino]-pyridin-3-yl}-cyclopropanecarboxylic Acid ethyl ester

The title compound is prepared from (1S,2S)-2-[6-(4-bromo-2,4-difluoro-benzylamino)-pyridin-3-yl]-cyclopropanecarboxylic acid ethyl ester and bis(pinacolato)diboron following a procedure analogous to that described for Intermediate 7. LC (method 1): t_(R)=0.95 min; Mass spectrum (ESI⁺): m/z=459 [M+H]⁺.

Intermediate 11 (1S,2S)-2-{6-[(5-Bromo-4-trifluoromethyl-benzyl)-tert-butoxycarbonyl-amino]-pyridin-3-yl}-cyclopropanecarboxylic Acid ethyl ester

The title compound is prepared from (1S,2S)-2-(6-tert-butoxycarbonylamino-pyridin-3-yl)-cyclopropanecarboxylic acid ethyl ester and 2-bromo-4-bromomethyl-1-trifluoromethyl-benzene (for preparation see WO2011/146324) following a procedure analogous to that described for Intermediate 5. LC (method 1): t_(R)=1.27 min; Mass spectrum (ESI⁺): m/z=543/545 (Br) [M+H]⁺.

Intermediate 12 (1S,2S)-2-[6-(3-Bromo-4-trifluoromethyl-benzylamino)-pyridin-3-yl]-cyclopropanecarboxylic Acid ethyl ester

The title compound is prepared from (1S,2S)-2-{6-[(5-bromo-4-trifluoromethyl-benzyl)-tert-butoxycarbonyl-amino]-pyridin-3-yl}-cyclopropanecarboxylic acid ethyl ester following a procedure analogous to that described for Intermediate 6. LC (method 1): t_(R)=0.91 min; Mass spectrum (ESI⁺): m/z=443/445 (Br) [M+H]⁺.

Intermediate 13 (1S,2S)-2-(6-{tert-Butoxycarbonyl-[4′-(3-methanesulfonyl-propoxy)-2′,6′-dimethyl-biphenyl-3-ylmethyl]-amino}-pyridin-3-yl)-cyclopropanecarboxylic Acid

The title compound is prepared from (1S,2S)-2-(6-tert-butoxycarbonylamino-pyridin-3-yl)-cyclopropanecarboxylic acid ethyl ester and methanesulfonic acid 4′-(3-methanesulfonyl-propoxy)-2′,6′-dimethyl-biphenyl-3-yl-methyl ester (for preparation see WO2012/111849) following a procedure analogous to that described for Intermediate 5. The title compound is obtained upon hydrolysis of the ester group. LC (method 2): t_(R)=1.12 min; Mass spectrum (ESI⁺): m/z=609 [M+H]⁺.

Example 1 (1S,2S)-2-(6-{([4-Fluoro-4′-(3-hydroxy-3-methyl-butoxy)-2′,6′-dimethyl-biphenyl-3-ylmethyl]-amino}-pyridin-3-yl)-cyclopropanecarboxylic Acid

A vial charged with a stir bar, 4-(4-bromo-3,5-dimethyl-phenoxy)-2-methyl-butan-2-ol (0.10 g), (1S,2S)-2-{6-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylamino]-pyridin-3-yl}-cyclopropanecarboxylic acid ethyl ester (0.15 g), K₃PO₄ (0.18 g), water (1.5 mL), and 1,4-dioxane (1.5 mL) is purged with Ar for 10 min. Bis[di-tert-butyl-(4-dimethylaminophenyl)-phosphine]dichloropalladium(II) (2.4 mg; PdCl₂(Amphos)₂) is added, the vial is sealed, and the mixture is stirred at 80° C. for 3 h. After cooling to room temperature, water is added, and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are concentrated, and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→3:7) to give the ethyl ester of the title compound. The ester (0.13 g) is dissolved in methanol (2 mL) and treated with aqueous 1 M NaOH solution (0.8 mL). The mixture is stirred at room temperature overnight. The mixture is neutralized with 1 M hydrochloric acid, filtered, and submitted to HPLC (MeCN/H₂O/F₃CCO₂H as eluent) to give the title compound. LC (method 1): t_(R)=0.89 min; Mass spectrum (ESI⁻): m/z=491 [M−H]⁻.

Example 2 (1S,2S)-2-(6-{([4,6-Difluoro-4′-(3-hydroxy-3-methyl-butoxy)-2′,6′-dimethyl-biphenyl-3-ylmethyl]-amino}-pyridin-3-yl)-cyclopropanecarboxylic Acid

The title compound is prepared from (1S,2S)-2-{6-[2,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylamino]-pyridin-3-yl}-cyclopropanecarboxylic acid ethyl ester and 4-(4-bromo-3,5-dimethyl-phenoxy)-2-methyl-butan-2-ol following a procedure analogous to that described for Example 1. LC (method 1): t_(R)=0.89 min; Mass spectrum (ESI⁻): m/z=509 [M−H]⁻.

Example 3 (1S,2S)-2-{6-[(5′-Aminomethyl-4,6,2′-trifluoro-biphenyl-3-ylmethyl)-amino]-pyridin-3-yl}-cyclopropanecarboxylic Acid

The title compound is prepared from (1S,2S)-2-{6-[2,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylamino]-pyridin-3-yl}-cyclopropanecarboxylic acid ethyl ester and 3-bromo-4-fluoro-benzylamine following a procedure analogous to that described for Example 1. LC (method 1): t_(R)=0.69 min; Mass spectrum (ESI⁺): m/z=428 [M+H]⁺.

Example 4 (1S,2S)-2-(6-{[4′-(3-Hydroxy-3-methyl-butoxy)-6-trifluoromethyl-biphenyl-3-ylmethyl]-amino}-pyridin-3-yl)-cyclopropanecarboxylic Acid

A vial charged with a stir bar, 2-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-butan-2-ol (35 mg), (1S,2S)-2-[6-(3-bromo-4-trifluoromethyl-benzylamino)-pyridin-3-yl]-cyclopropanecarboxylic acid ethyl ester (50 mg), K₃PO₄ (100 mg), water (0.5 mL), and 1,4-dioxane (0.5 mL) is purged with Ar for 10 min. Bis[di-tert-butyl-(4-dimethylaminophenyl)-phosphine]dichloropalladium(II) (3 mg; PdCl₂(Amphos)₂) is added, the vial is sealed, and the mixture is stirred at 90° C. for 3 h. After cooling to room temperature, aqueous 1 M NaOH solution (0.5 mL) is added, and the mixture is stirred at room temperature for 1 h. The mixture is filtered and submitted to HPLC (MeCN/H₂O/F₃CCO₂H as eluent) to give the title compound. LC (method 1): t_(R)=0.89 min; Mass spectrum (ESI⁻): m/z=513 [M−H]⁻.

Example 5 (1S,2S)-2-(6-{[4′-(3-Hydroxy-3-methyl-butoxy)-2′,6′-dimethyl-6-trifluoromethyl-biphenyl-3-ylmethyl]-amino}-pyridin-3-yl)-cyclopropanecarboxylic Acid

The title compound is prepared from (1S,2S)-2-[6-(3-bromo-4-trifluoromethyl-benzylamino)-pyridin-3-yl]-cyclopropanecarboxylic acid ethyl ester and [4-(3-hydroxy-3-methyl-butyloxy)-phenylboronic acid following a procedure analogous to that described for Example 4. LC (method 1): t_(R)=0.92 min; Mass spectrum (ESI⁻): m/z=541 [M−H]⁻.

Example 6 (1S,2S)-2-{6-[(4′-Trifluoromethoxy-6-trifluoromethyl-biphenyl-3-ylmethyl)-amino]-pyridin-3-yl}-cyclopropanecarboxylic Acid

The title compound is prepared from (1S,2S)-2-[6-(3-bromo-4-trifluoromethyl-benzylamino)-pyridin-3-yl]-cyclopropanecarboxylic acid ethyl ester and 4-trifluoromethoxy-phenylboronic acid following a procedure analogous to that described for Example 4. LC (method 1): t_(R)=0.97 min; Mass spectrum (ESI⁻): m/z=495 [M−H]⁻.

Example 7 (1S,2S)-2-{6-[(4′-Cyclopropylmethoxy-6-trifluoromethyl-biphenyl-3-ylmethyl)-amino]-pyridin-3-yl}-cyclopropanecarboxylic acid

The title compound is prepared from (1S,2S)-2-[6-(3-bromo-4-trifluoromethyl-benzylamino)-pyridin-3-yl]-cyclopropanecarboxylic acid ethyl ester and 4-cyclopropylmethoxy-phenylboronic acid following a procedure analogous to that described for Example 4. LC (method 1): t_(R)=0.97 min; Mass spectrum (ESI⁻): m/z=481 [M−H]⁻.

Example 8 (1S,2S)-2-(6-{[4′-(3-Methanesulfonyl-propoxy)-2′,6′-dimethyl-biphenyl-3-ylmethyl]-amino}-pyridin-3-yl)-cyclopropanecarboxylic Acid

The title compound is prepared from (1S,2S)-2-(6-{tert-butoxycarbonyl-[4′-(3-methanesulfonyl-propoxy)-2′,6′-dimethyl-biphenyl-3-ylmethyl]-amino}-pyridin-3-yl)-cyclopropanecarboxylic acid following a procedure analogous to that described for Intermediate 6. LC (method 2): t_(R)=0.84 min; Mass spectrum (ESI⁻): m/z=509 [M+H]⁺.

The following compounds may be obtained from (1S,2S)-2-{6-[2-fluoro-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-benzylamino]-pyridin-3-yl}-cyclopropane-carboxylic acid ethyl ester or (1S,2S)-2-{6-[2,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylamino]-pyridin-3-yl}-cyclopropanecarboxylic acid ethyl ester and the bromide (or chloride or iodide) of the respective coupling partner following the procedure described for Example 1 or Example 4.

Typical Procedure:

A vial charged with a stir bar, (1S,2S)-2-{6-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylamino]-pyridin-3-yl}-cyclopropane-carboxylic acid ethyl ester or (1S,2S)-2-{6-[2,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylamino]-pyridin-3-yl}-cyclopropanecarboxylic acid ethyl ester (0.1 mmol, 1 eq.), the coupling partner as bromide (0.1 mmol, 1 eq.), 2 M aqueous K₃PO₄ solution (0.25 mmol, 2.5 eq.), and 1,4 dioxane (1 mL) is purged with Ar for 10 min. Bis[di-tert-butyl-(4-dimethylaminophenyl)-phosphine]dichloropalladium(II) (PdCl₂(Amphos)₂); 0.001 mmol, 1 mol %) is added, and the mixture is stirred at 80° C. until the starting boronic ester is completely consumed (by TLC or HPLC). After cooling to room temperature, the mixture is filtered over RP18 silica gel and diluted with methanol (3 mL). 4 M aqueous NaOH solution (1.6 mmol, ca. 16 eq.) is added, and the mixture is stirred at room temperature for 3 h. The mixture is acidified with 50% trifluoroacetic acid and chromatographed (HPLC on reversed phase, acetonitrile/water/trifluoroacetic acid) to give the corresponding carboxylic acid with an enantiomeric excess of 80% to 98% depending on the enantiomeric purity of the starting material.

Alternatively, the transition metal catalyzed coupling and the saponification of the resulting ester are carried out in the same reaction vessel without work-up in between by adding the aqueous base to the mixture of the coupling reaction after complete consumption of the boronic ester at room temperature.

R^(L) Retention time on HPLC (method) Example (coupling partner is R^(L)—Br) Mass spectrum (MS)  9

LC (method 2): t_(R) = 0.90 min MS (ESI⁻): m/z = 458 [M − H]⁻ 10

LC (method 2): t_(R) = 0.85 min MS (ESI⁻): mz = 430 [M + H]⁻ 11

LC (method 2): t_(R) = 0.89 min MS (ESI⁻): m/z = 467 [M − H]⁻ 12

LC (method 2): t_(R) = 0.87 MS (ESI⁻): m/z = 525 [M − H]⁻ 13

LC (method 2): t_(R) = 0.86 MS (ESI⁻): m/z = 498 [M + H]⁻ 14

LC (method 2): t_(R) = 0.89 MS (ESI⁻): m/z = 531 [M + H]⁻ 15

LC (method 2): t_(R) = 0.83 MS (ESI⁻): m/z = 407 [M + H]⁺ 16

LC (method 2): t_(R) = 0.93 MS (ESI⁻): m/z = 537 [M + H]⁺ 17

  (4-bromo-3,5-dimethyl-phenoxy)- acetic acid methyl ester used LC (method 2): t_(R) = 0.84 MS (ESI⁻): m/z = 465 [M + H]⁺ 18

LC (method 3): t_(R) = 0.66 MS (ESI⁻): m/z = 391 [M + H]⁺ 19

LC (method 3): t_(R) = 0.65 MS (ESI⁻): m/z = 429 [M + H]⁺ 20

LC (method 3): t_(R) = 0.61 MS (ESI⁻): m/z = 399 [M + H]⁺ 21

LC (method 3): t_(R) = 0.70 MS (ESI⁻): m/z = 499 [M + H]⁺ 22

LC (method 3): t_(R) = 0.67 MS (ESI⁻): m/z = 465 [M + H]⁺ 23

LC (method 3): t_(R) = 0.52 MS (ESI⁻): m/z = 413 [M + H]⁺ 24

  iodide instead of bromide used (R^(L)—I) LC (method 3): t_(R) = 0.66 MS (ESI⁻): m/z = 431 [M + H]⁺ 25

  iodide instead of bromide used (R^(L)—I) LC (method 3): t_(R) = 0.71 MS (ESI⁻): m/z = 445 [M + H]⁺ 26

LC (method 3): t_(R) = 0.67 MS (ESI⁻): m/z = 421 [M + H]⁺ 27

  4-chloro-3,5-dimethyl-benzoic acid methyl ester used LC (method 3): t_(R) = 0.57 MS (ESI⁻): m/z = 435 [M + H]⁺ 28

LC (method 3): t_(R) = 0.54 MS (ESI⁻): m/z = 414 [M + H]⁺ 29

LC (method 3): t_(R) = 0.71 MS (ESI⁻): m/z = 455 [M + H]⁺ 30

LC (method 3): t_(R) = 0.62 MS (ESI⁻): m/z = 453 [M + H]⁺ 31

  iodide instead of bromide used (R^(L)—I) LC (method 3): t_(R) = 0.66 MS (ESI⁻): m/z = 431 [M + H]⁺ 32

LC (method 3): t_(R) = 0.61 MS (ESI⁻): m/z = 428 [M + H]⁺ 33

  iodide instead of bromide used (R^(L)—I) LC (method 3): t_(R) = 0.66 MS (ESI⁻): m/z = 491 [M + H]⁺ 34

LC (method 3): t_(R) = 0.51 MS (ESI⁻): m/z = 434 [M + H]⁺ 35

LC (method 3): t_(R) = 0.65 MS (ESI⁻): m/z = 416 [M + H]⁺ 36

LC (method 3): t_(R) = 0.69 MS (ESI⁻): m/z = 491 [M + H]⁺ 37

LC (method 3): t_(R) = 0.66 MS (ESI⁻): m/z = 491 [M + H]⁺ 38

LC (method 3): t_(R) = 0.66 MS (ESI⁻): m/z = 477 [M + H]⁺ 39

LC (method 3): t_(R) = 0.63 MS (ESI⁻): m/z = 477 [M + H]⁺ 40

LC (method 3): t_(R) = 0.56 MS (ESI⁻): m/z = 417 [M + H]⁺ 41

LC (method 3): t_(R) = 0.65 MS (ESI⁻): m/z = 421 [M + H]⁺ 42

LC (method 3): t_(R) = 0.69 MS (ESI⁻): m/z = 491 [M + H]⁺ 43

  iodide instead of bromide used (R^(L)—I) LC (method 3): t_(R) = 0.58 MS (ESI⁻): m/z = 499 [M + H]⁺ 44

LC (method 3): t_(R) = 0.6 MS (ESI⁻): m/z = 498 [M + H]⁺ 45

LC (method 3): t_(R) = 0.6 MS (ESI⁻): m/z = 491 [M + H]⁺ 46

LC (method 3): t_(R) = 0.72 MS (ESI⁻): m/z = 488 [M + H]⁺ 47

LC (method 3): t_(R) = 0.81 MS (ESI⁻): m/z = 497 [M + H]⁺ 48

LC (method 3): t_(R) = 0.65 MS (ESI⁻): m/z = 473 [M + H]⁺ 49

  iodide instead of bromide used (R^(L)—I) LC (method 3): t_(R) = 0.52 MS (ESI⁻): m/z = 499 [M + H]⁺ 50

LC (method 3): t_(R) = 0.64 MS (ESI⁻): m/z = 471 [M + H]⁺ 51

LC (method 3): t_(R) = 0.74 MS (ESI⁻): m/z = 149 [M + H]⁺ 52

LC (method 3): t_(R) = 0.62 MS (ESI⁻): m/z = 459 [M + H]⁺ 53

LC (method 3): t_(R) = 0.69 MS (ESI⁻): m/z = 483 [M + H]⁺ 54

LC (method 3): t_(R) = 0.71 MS (ESI⁻): m/z = 405 [M + H]⁺ 55

LC (method 3): t_(R) = 0.61 MS (ESI⁻): m/z = 521 [M + H]⁺ 56

LC (method 3): t_(R) = 0.65 MS (ESI⁻): m/z = 489 [M + H]⁺ 57

LC (method 3): t_(R) = 0.59 MS (ESI⁻): m/z = 569 [M + H]⁺ 58

LC (method 3): t_(R) = 0.73 MS (ESI⁻): m/z = 505 [M + H]⁺ 59

LC (method 2): t_(R) = 0.82 MS (ESI⁻): m/z = 448 [M + H]⁺ 60

LC (method 2): t_(R) = 0.84 MS (ESI⁻): m/z = 462 [M + H]⁺

R^(L) Retention time on HPLC (method) Example (coupling partner is R^(L)—Br) Mass spectrum (MS)  61

LC (method 3): t_(R) = 0.67 MS (ESI⁻): m/z = 409 [M + H]⁺  62

LC (method 4): t_(R) = 0.49 MS (ESI⁻): m/z = 447 [M + H]⁺  63

LC (method 3): t_(R) = 0.63 MS (ESI⁻): m/z = 417 [M + H]⁺  64

LC (method 3): t_(R) = 0.69 MS (ESI⁻): m/z = 483 [M + H]⁺  65

LC (method 3): t_(R) = 0.55 MS (ESI⁻): m/z = 431 [M + H]⁺  66

  iodide instead of bromide used (R^(L)—I) LC (method 3): t_(R) = 0.67 MS (ESI⁻): m/z = 449 [M + H]⁺  67

  iodide instead of bromide used (R^(L)—I) LC (method 3): t_(R) = 0.71 MS (ESI⁻): m/z = 463 [M + H]⁺  68

LC (method 3): t_(R) = 0.68 MS (ESI⁻): m/z = 439 [M + H]⁺  69

LC (method 4): t_(R) = 0.27 MS (ESI⁻): m/z = 453 [M + H]⁺  70

LC (method 3): t_(R) = 0.56 MS (ESI⁻): m/z = 432 [M + H]⁺  71

LC (method 3): t_(R) = 0.72 MS (ESI⁻): m/z = 473 [M + H]⁺  72

LC (method 3): t_(R) = 0.62 MS (ESI⁻): m/z = 471 [M + H]⁺  73

  iodide instead of bromide used (R^(L)—I) LC (method 3): t_(R) = 0.67 MS (ESI⁻): m/z = 449 [M + H]⁺  74

LC (method 3): t_(R) = 0.62 MS (ESI⁻): m/z = 446 [M + H]⁺  75

  iodide instead of bromide used (R^(L)—I) LC (method 3): t_(R) = 0.67 MS (ESI⁻): m/z = 509 [M + H]⁺  76

LC (method 4): t_(R) = 0.4 MS (ESI⁻): m/z = 452 [M + H]⁺  77

LC (method 3): t_(R) = 0.66 MS (ESI⁻): m/z = 434 [M + H]⁺  78

LC (method 3): t_(R) = 0.70 MS (ESI⁻): m/z = 509 [M + H]⁺  79

LC (method 3): t_(R) = 0.66 MS (ESI⁻): m/z = 495 [M + H]⁺  80

LC (method 3): t_(R) = 0.66 MS (ESI⁻): m/z = 495 [M + H]⁺  81

LC (method 3): t_(R) = 0.65 MS (ESI⁻): m/z = 435 [M + H]⁺  82

LC (method 3): t_(R) = 0.43 MS (ESI⁻): m/z = 439 [M + H]⁺  83

LC (method 3): t_(R) = 0.66 MS (ESI⁻): m/z = 497 [M + H]⁺  84

LC (method 3): t_(R) = 0.52 MS (ESI⁻): m/z = 509 [M + H]⁺  85

  iodide instead of bromide used (R^(L)—I) LC (method 3): t_(R) = 0.59 MS (ESI⁻): m/z = 517 [M + H]⁺  86

LC (method 3): t_(R) = 0.60 MS (ESI⁻): m/z = 516 [M + H]⁺  87

LC (method 4): t_(R) = 0.53 MS (ESI⁻): m/z = 509 [M + H]⁺  88

LC (method 3): t_(R) = 0.73 MS (ESI⁻): m/z = 506 [M + H]⁺  89

LC (method 3): t_(R) = 0.81 MS (ESI⁻): m/z = 515 [M + H]⁺  90

LC (method 3): t_(R) = 0.66 MS (ESI⁻): m/z = 491 [M + H]⁺  91

  iodide instead of bromide used (R^(L)—I) LC (method 4): t_(R) = 0.54 MS (ESI⁻): m/z = 517 [M + H]⁺  92

LC (method 3): t_(R) = 0.65 MS (ESI⁻): m/z = 489 [M + H]⁺  93

LC (method 3): t_(R) = 0.74 MS (ESI⁻): m/z = 437 [M + H]⁺  94

LC (method 3): t_(R) = 0.63 MS (ESI⁻): m/z = 477 [M + H]⁺  95

LC (method 3): t_(R) = 0.70 MS (ESI⁻): m/z = 501 [M + H]⁺  96

LC (method 3): t_(R) = 0.72 MS (ESI⁻): m/z = 423 [M + H]⁺  97

LC (method 3): t_(R) = 0.62 MS (ESI⁻): m/z = 539 [M + H]⁺  98

LC (method 4): t_(R) = 0.54 MS (ESI⁻): m/z = 555 [M + H]⁺  99

LC (method 3): t_(R) = 0.66 MS (ESI⁻): m/z = 516 [M + H]⁺ 100

LC (method 3): t_(R) = 0.59 MS (ESI⁻): m/z = 587 [M + H]⁺ 101

LC (method 3): t_(R) = 0.73 MS (ESI⁻): m/z = 523 [M + H]⁺ 102

LC (method 2): t_(R) = 0.82 MS (ESI⁻): m/z = 466 [M + H]⁺ 103

LC (method 2): t_(R) = 0.85 MS (ESI⁻): m/z = 480 [M + H]⁺ 

The invention claimed is:
 1. A compound of formula (I)

wherein R is selected from the group consisting of H, F, Cl, Br, I, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, NC—, HNR^(N)—C(═O)—, C₁₋₄-alkyl-NR^(N)—C(═O)—, C₃₋₆-cycloalkyl-NR^(N)—C(═O)—, heterocyclyl-NR^(N)—C(═O)—, heteroaryl-NR^(N)—C(═O)—, HOOC—, C₁₋₄-alkyl-O—C(═O)—, O₂N—, HR^(N)N—, C₁₋₄-alkyl-R^(N)N—, C₁₋₄-alkyl-C(═O)NR^(N)—, C₃₋₆-cycloalkyl-C(═O)NR^(N)—, heterocyclyl-C(═O)NR^(N)—, heteroaryl-C(═O)NR^(N)—, C₁₋₄-alkyl-S(═O)₂NR^(N)—, C₃₋₆-cycloalkyl-S(═O)₂NR^(N)—, heterocyclyl-S(═O)₂NR^(N)—, heteroaryl-S(═O)₂NR^(N)—, HO—, C₁₋₆-alkyl-O—, HOOC—C₁₋₃-alkyl-O—, C₃₋₆-cycloalkyl-C₁₋₃-alkyl-O—, heterocyclyl-C₁₋₃-alkyl-O—, phenyl-C₁₋₃-alkyl-O—, C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, heteroaryl-O—, C₁₋₄-alkyl-S—, C₃₋₆-cycloalkyl-S—, heterocyclyl-S—, C₁₋₄-alkyl-S(═O)—, C₃₋₆-cycloalkyl-S(═O)—, heterocyclyl-S(═O)—, C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl-S(═O)₂—, heterocyclyl-S(═O)₂—, phenyl-S(═O)₂—, heteroaryl-S(═O)₂—, HNR^(N)—S(═O)₂—, C₁₋₄-alkyl-NR^(N)—S(═O)₂—, heterocyclyl, phenyl, and heteroaryl, wherein each alkyl, cycloalkyl, and heterocyclyl group or sub-group within the groups forming R is optionally substituted with 1 or more F atoms and optionally substituted with 1 to 3 groups independently selected from Cl, C₁₋₃-alkyl, NC—, (R^(N))₂N—, HO—, C₁₋₃-alkyl-O—, and C₁₋₃-alkyl-S(═O)₂—; and wherein each phenyl and heteroaryl group or sub-group within the groups forming R is optionally substituted with 1 to 5 substituents independently selected from F, Cl, C₁₋₃-alkyl, HF₂C—, F₃C—, NC—, (R^(N))₂N—, HO—, C₁₋₃-alkyl-O—, F₃C—O—, and C₁₋₃-alkyl-S(═O)₂—; wherein each heterocyclyl group or sub-group within the groups forming R is selected from a cyclobutyl group wherein 1 CH₂ group is replaced by —NR^(N)— or —O—; a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is replaced by —C(═O)—, —NR^(N)—, —O—, —S— or —S(═O)₂— and/or 1 CH group is replaced by N; a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is replaced by —NR^(N)— or —O—, a second CH₂ group is replaced by —NR^(N)—, —C(═O)— or —S(═O)₂— and/or 1 CH group is replaced by N; and a C₅₋₆-cycloalkyl group wherein 2 CH₂ groups are replaced by —NR^(N)— or 1 CH₂ group by —NR^(N)— and the other by —O— and a third CH₂ group is replaced by —C(═O)— or —S(═O)₂— and/or 1 CH group is replaced by N; wherein each heteroaryl group or sub-group within the groups forming R is selected from tetrazolyl and a 5- or 6-membered heteroaromatic ring which contains 1, 2, or 3 heteroatoms independently of each other selected from ═N—, —NR^(N)—, —O—, and —S—, wherein in heteroaromatic groups containing a —HC═N— unit this group is optionally replaced by —NR^(N)—C(═O)—; wherein in heteroaryl and heterocyclyl rings with one or more NH groups, each of said NH groups is replaced by NR^(N); R¹ is selected from the group consisting of H, F, Cl, C₁₋₄-alkyl, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkyl, C₁₋₄-alkyl-O—C₁₋₄-alkyl, NC—, HO—, C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O—, C₁₋₄-alkyl-S—, C₁₋₄-alkyl-S(O)—, and C₁₋₄-alkyl-S(O)₂—, wherein any alkyl and cycloalkyl group or sub-group within the groups forming R¹ is optionally substituted with 1 or more F atoms, and wherein multiple R¹ may be identical or different if m is 2, 3 or 4; m is an integer selected from 1, 2, 3, and 4; R² is selected from the group consisting of H, F, Cl, C₁₋₄-alkyl, NC—, and C₁₋₄-alkyloxy, wherein any alkyl group or sub-group within the groups forming R² is optionally substituted with 1 or more F atoms, and wherein multiple R² may be identical or different if n is 2 or 3; R³ is selected from the group consisting of H, F, Cl, C₁₋₄-alkyl, NC—, and C₁₋₄-alkyl-O—, wherein each alkyl group or sub-group within the groups forming R³ is optionally substituted with 1 or more F atoms; n is an integer selected from 1, 2, and 3; R^(N) is independently of each other selected from the group consisting of H, C₁₋₄-alkyl, HO—C₁₋₄-alkyl-(H₂C)—, C₁₋₃-alkyl-O—C₁₋₄-alkyl-, C₁₋₄-alkyl-C(═O)—, C₁₋₄-alkyl-NH—C(═O)—, C₁₋₄-alkyl-N(C₁₋₄-alkyl)-C(═O)—, C₁₋₄-alkyl-O—C(═O)—, and C₁₋₄-alkyl-S(═O)₂—, wherein each alkyl group or sub-group within the groups forming R^(N) is optionally substituted with 1 or more F atoms; wherein in any definition mentioned hereinbefore, if not specified otherwise, any alkyl group or sub-group may be straight-chained or branched, or a salt thereof.
 2. The compound according to claim 1, wherein R is selected from the group consisting of H, F, Cl, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, NC—, HNR^(N)—C(═O)—, C₁₋₄-alkyl-NR^(N)—C(═O)—, C₃₋₆-cycloalkyl-NR^(N)—C(═O)—, heterocyclyl-NR^(N)—C(═O)—, HOOC—, HR^(N)N—, C₁₋₄-alkyl-R^(N)N—, C₁₋₄-alkyl-C(═O)NR^(N)—, C₃₋₆-cycloalkyl-C(═O)NR^(N)—, heterocyclyl-C(═O)NR^(N)—, C₁₋₄-alkyl-S(═O)₂NR^(N)—, HO—, C₁₋₆-alkyl-O—, HOOC—(C₁₋₂-alkyl)-O—, cyclopropyl-H₂C—O—, heterocyclyl-C₁₋₂-alkyl-O—, phenyl-C₁₋₂-alkyl-O—, C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, heteroaryl-O—, C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl-S(═O)₂—, heterocyclyl-S(═O)₂—, HNR^(N)—S(═O)₂—, C₁₋₄-alkyl-NR^(N)—S(═O)₂—, heterocyclyl, and heteroaryl, wherein each alkyl, cycloalkyl, and heterocyclyl group or sub-group within the groups forming R is optionally substituted with 1 or more F atoms and optionally substituted with 1 to 2 groups independently selected from Cl, H₃C—, NC—, R^(N)HN—, HO—, H₃C—O—, and H₃C—S(═O)₂—; wherein each heteroaryl group or sub-group within the groups forming R is optionally substituted with 1 to 3 substituents independently selected from F, Cl, H₃C—, F₃C—, NC—, (R^(N))₂N—, HO—, H₃C—O—, F₃C—O—, and H₃C—S(═O)₂—; wherein each heterocyclyl group or sub-group within the groups forming R is selected from a cyclobutyl group wherein 1 CH₂ group is replaced by —NR^(N)— or —O—; a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is replaced by —C(═O)—, —NR^(N)—, —O—, —S— or —S(═O)₂— and/or 1 CH group is replaced by N; a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is replaced by —NR^(N)— or —O—, a second CH₂ group is replaced by —NR^(N)—, —C(═O)— or —S(═O)₂— and/or 1 CH group is replaced by N; wherein each heteroaryl group or sub-group within the groups forming R is selected from tetrazolyl, a 5-membered heteroaromatic ring which contains 1, 2 or 3 heteroatoms independently of each other selected from ═N—, —NH—, O and S, and a 6-membered heteroaromatic ring which contains 1 or 2 ═N— atoms, wherein a —HC═N— unit is optionally replaced by —NH—C(═O)—; and wherein in each of the above heteroaryl and heterocyclyl group or sub-group containing one or more NH, said group(s) is replaced by NR^(N); or a salt thereof.
 3. The compound according to claim 1, wherein R is selected from the group consisting of H, F, Cl, NC—, H₂NC(═O)—, H₃CHN—C(═O)—, (H₃C)₂N—C(═O)—, HO—; C₁₋₃-alkyl is optionally substituted with 1 or more F or optionally monosubstituted with HO—; cyclopropyl optionally monosubstituted with NC—; H₃C—O— optionally monosubstituted with C₁₋₄-alkyl, HOOC—, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, or phenyl, wherein the C₁₋₄-alkyl group optionally attached to H₃C—O— is optionally monosubstituted with NC—, HO— or H₃C—S(═O)₂—, and wherein said oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl and 1,1-dioxotetrahydrothiopyranyl groups are optionally monosubstituted with H₃C— or HO—; cyclopropyl-H₂C—O—, cyclopropyl-O—, tetrahydrofuranyl-O— and tetrahydropyranyl-O—; and a heteroaryl group selected from pyrazolyl, [1,2,4]oxadiazolyl, tetrazolyl, pyridyl, pyridin-2-onyl, pyrazinyl, pyrimidinyl, pyrimidin-2-onyl, and pyrimidin-4-onyl, wherein each of said heteroaryl groups is optionally monosubstituted with H₃C—, and wherein each H—N group in said heteroaryl groups is optionally replaced with H₃C—N or (H₃C)₂C(OH)—H₂C—N, and 2-methoxypyridin-4-yl; or a salt thereof.
 4. The compound according to claim 1, wherein R¹ is H, F, Cl, H₃C—, H₃C—H₂C—, (H₃C)₂HC—, F₃C—, or H₃C—O—; m is 2; R² is H, F, or F₃C—; n is 1 or 2; and R³ is H; or a salt thereof.
 5. The compound according to claim 1, wherein R¹ is H₃C—; or a salt thereof.
 6. The compound according to claim 1, wherein R is selected from the group consisting of H, F, Cl, NC—, H₂NC(═O)—, H₃CHN—C(═O)—, (H₃C)₂N—C(═O)—, HO—; C₁₋₃-alkyl optionally substituted with 1 or more F or optionally monosubstituted with HO—; cyclopropyl optionally monosubstituted with NC—; H₃C—O— optionally monosubstituted with C₁₋₄-alkyl, HOOC—, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, or phenyl, wherein the C₁₋₄-alkyl group optionally attached to H₃C—O— is optionally monosubstituted with NC—, HO— or H₃C—S(═O)₂—, and wherein said oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl and 1,1-dioxotetrahydrothiopyranyl groups are optionally monosubstituted with H₃C— or HO—; cyclopropyl-H₂C—O—, cyclopropyl-O—, tetrahydrofuranyl-O— and tetrahydropyranyl-O—; and a heteroaryl group selected from pyrazolyl, [1,2,4]oxadiazolyl, tetrazolyl, pyridyl, pyridin-2-onyl, pyrazinyl, pyrimidinyl, pyrimidin-2-onyl, and pyrimidin-4-onyl, wherein each of said heteroaryl groups is optionally monosubstituted with H₃C—, and wherein each H—N group in said heteroaryl groups is optionally replaced with H₃C—N or (H₃C)₂C(OH)—H₂C—N, and 2-methoxypyridin-4-yl; R¹ is selected from the group consisting of H, F, Cl, H₃C—, H₃C—H₂C—, (H₃C)₂HC—, F₃C—, and H₃C—O—; m is 2; R² is selected from the group consisting of H, F, and F₃C—; n is 1 or 2; and R³ is selected from the group consisting of H; or a salt thereof.
 7. The compound according to claim 1, wherein R is selected from the group consisting of H, F, Cl, H₃C—, H₃C—H₂C—, (H₃C)₂CH—,

F₃C—, HOCH₂—, NC—, H₂N—C(═O)—, H₃C—NH—C(═O)—, (H₃C)₂N—C(═O)—, H₃C—O—, cyclopropyl-H₂C—O—, F₃C—O—, cyclopropyl-O—,

wherein the asterisk (-*) indicates the site/point of attachment; R¹ is selected from the group consisting of H₃C—; m is 2; R² is selected from the group consisting of H, F, and F₃C—; n is 1 or 2; and R³ is selected from the group consisting of H; or a salt thereof.
 8. The compound according to claim 1, with the structure and stereochemistry shown in formulae I.1, I.2, I.3, or I.4

or a salt thereof.
 9. A pharmaceutically acceptable salt of a compound according to claim
 1. 10. A pharmaceutical composition comprising one or more compounds according to claim 1 or one or more pharmaceutically acceptable salts thereof, optionally together with one or more inert carriers and/or diluents.
 11. A pharmaceutical composition comprising one or more compounds according to claim 1 or one or more pharmaceutically acceptable salts thereof and one or more additional therapeutic agents, optionally together with one or more inert carriers and/or diluents.
 12. The pharmaceutical composition according to claim 11 wherein the one or more additional therapeutic agents is selected from the group consisting of antidiabetic agents, agents for the treatment of overweight and/or obesity and agents for the treatment of high blood pressure, heart failure and/or atherosclerosis.
 13. A method for treating a disease or condition which can be influenced by the modulation of the function of GPR40, the method comprising administering to a patient in need thereof, a compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the disease or condition is a metabolic disease selected from type 2 diabetes mellitus, insulin resistance, obesity, cardiovascular disease and dyslipidemia. 